Sulfonamide derivatives

ABSTRACT

The present invention relates to compounds of the formula 
                         
and pharmaceutically acceptable salts, solvates or tautomers thereof, to processes for the preparation of, intermediates used in the preparation of, and compositions containing such compounds, and the uses of such compounds, in particular for the treatment of pain.

CROSS REFERENCE

This application is a continuation of U.S. patent application Ser. No.12/685,913 filed Jan. 12, 2010, which claims benefit under 35 USC 119(e)of U.S. Provisional Application 61/143,920, filed Jan. 12, 2009; U.S.Provisional Application 61/245,726, filed Sep. 25, 2009; and U.S.Provisional Application 61/258,760, filed Nov. 6, 2009.

This invention relates to sulfonamide derivatives. More particularly,this invention relates to heteroaryl substituted sulphonamidederivatives and to processes for the preparation of, intermediates usedin the preparation of, compositions containing, and the uses of, suchderivatives.

The sulfonamide derivatives of the present invention are sodium channelmodulators and have a number of therapeutic applications, particularlyin the treatment of pain.

Voltage-gated sodium channels are found in all excitable cells includingmyocytes of muscle and neurons of the central and peripheral nervoussystem. In neuronal cells, sodium channels are primarily responsible forgenerating the rapid upstroke of the action potential. In this mannersodium channels are essential to the initiation and propagation ofelectrical signals in the nervous system. Proper and appropriatefunction of sodium channels is therefore necessary for normal functionof the neuron. Consequently, aberrant sodium channel function is thoughtto underlie a variety of medical disorders (see Hubner C A, Jentsch T J,Hum. Mol. Genet., 11(20): 2435-45 (2002) for a general review ofinherited ion channel disorders) including epilepsy (Yogeeswari et al.,Curr. Drug Targets, 5(7): 589-602 (2004)), arrhythmia (Noble D., Proc.Natl. Acad. Sci. USA, 99(9): 5755-6 (2002)) myotonia (Cannon, S C,Kidney Int. 57(3): 772-9 (2000)), and pain (Wood, J N et al., J.Neurobiol., 61(1): 55-71 (2004)). See Table A, below.

TABLE A Gene Primary TTX Disease Type Symbol tissue IC-50 nM associationIndications Na_(v)1.1 SCN1A CNS/PNS 10 Epilepsy Pain, seizures,neurodegeneration Na_(v)1.2 SCN2A CNS 10 Epilepsy Epilepsy,neurodegeneration Na_(v)1.3 SCN3A CNS 15 — Pain Na_(v)1.4 SCN4A Sk.muscle 25 Myotonia Myotonia Na_(v)1.5 SCN5A Heart 2000 ArrhythmiaArrhythmia Na_(v)1.6 SCN8A CNS/PNS 6 — Pain, movement disordersNa_(v)1.7 SCN9A PNS 25 Erythermalgia Pain Na_(v)1.8 SCN10A PNS 50000 —Pain Na_(v)1.9 SCN11A PNS 1000 — Pain

There are currently at least nine known members of the family ofvoltage-gated sodium channel (VGSC) alpha subunits. Names for thisfamily include SCNx, SCNAx, and Na_(v)x.x. The VGSC family has beenphylogenetically divided into two subfamilies Na_(v)1.x (all but SCN6A)and Na_(v)2.x (SCN6A). The Nav1.x subfamily can be functionallysubdivided into two groups, those which are sensitive to blocking bytetrodotoxin (TTX-sensitive or TTX-s) and those which are resistant toblocking by tetrodotoxin (TTX-resistant or TTX-r).

There are three members of the subgroup of TTX-resistant sodiumchannels. The SCN5A gene product (Na_(v)1.5, H1) is almost exclusivelyexpressed in cardiac tissue, is thought to play a central role in thegeneration of the cardia action potential and propagation of electricalimpulses in the heart, and has also been shown to underlie a variety ofcardiac arrhythmias and conduction disorders (Liu H, et al., Am. J.Pharmacogenomics, 3(3): 173-9 (2003)). Consequently, blockers of Nav1.5have found clinical utility in treatment of such disorders (Srivatsa U,et al., Curr. Cardiol. Rep., 4(5): 401-10 (2002)), but binding of drugsto Nav1.5 may also result in abnormal cardiac rhythms. The remainingTTX-resistant sodium channels, Nav1.8 (SCN10A, PN3, SNS) and Nav1.9(SCN11A, NaN, SNS2) are expressed in the peripheral nervous system andshow preferential expression in primary nociceptive neurons. Humangenetic variants of these channels have not been associated with anyinherited clinical disorder. However, aberrant expression of Nav1.8 hasbeen found in the CNS of human multiple sclerosis (MS) patients and alsoin a rodent model of MS (Black, J A, et al., Proc. Natl. Acad. Sci. USA,97(21): 11598-602 (2000)). Evidence for involvement in nociception isboth associative (preferential expression in nociceptive neurons) anddirect (genetic knockout). Nav1.8-null mice exhibited typicalnociceptive behavior in response to acute noxious stimulation but hadsignificant deficits in referred pain and hyperalgesia (Laird J M, etal., J. Neurosci., 22(19):8352-6 (2002)).

The TTX-sensitive subset of voltage-gated sodium channels is expressedin a broader range of tissues than the TTX-resistant channels and hasbeen associated with a variety of human disorders. The Na_(v)1.1 channelwell exemplifies this general pattern, as it is expressed in both thecentral and peripheral nervous system and has been associated withseveral seizure disorders including Generalized Epilepsy with FebrileSeizures Plus, types 1 and 2 (GEFS+1, GEFS+2), Severe Myoclonic Epilepsyof Infancy (SMEI), and others (Claes, L, et al., Am. J. Hum. Genet., 68:1327-1332 (2001); Escayg, A., Am. J. Hum. Genet., 68: 866-873 (2001);Lossin, C, Neuron, 34: 877-884 (2002)). The Nav1.2 channel is largely,if not exclusively, expressed in the central nervous system andquantitative studies indicate it is the most abundant VGSC of the CNS.Mutations of Nav1.2 are also associated with seizure disorders(Berkovic, S. F., et al., Ann. Neurol., 55: 550-557 (2004)) andNav1.2-null “knockout” mice exhibit perinatal lethality (Planells-CasesR et al., Biophys. J., 78(6):2878-91 (2000)). Expression of the Nav1.4gene is largely restricted to skeletal muscle and, accordingly,mutations of this gene are associated with a variety of movementdisorders (Ptacek, L. J., Am. J. Hum. Genet., 49: 851-854 (1991); HudsonA J, Brain, 118(2): 547-63 (1995)). The majority of these disorders arerelated to hyperactivity or “gain-of-function” and have been found torespond to treatment with sodium channel blockers (Desaphy J F, et al.,J. Physiol., 554(2): 321-34 (2004)).

Neither the SCN3A nor the SCN8A VGSC genes have been conclusively linkedto heritable disorders in humans. Loss-of-function mutations of theSCN8A gene are known in mice and yield increasingly debilitatingphenotypes, dependent upon the remaining functionality of the geneproducts (Meisler M H, Genetica, 122(1): 37-45 (2004)). Homozygous nullmutations cause progressive motor neuron failure leading to paralysisand death, while heterozygous null animals are asymptomatic. Homozygousmed^(J) mice have nearly 90% reduction in functional Nav1.6 current andexhibit dystonia and muscle weakness but are still viable. Evidence forNav1.6 being important for nociception is largely associative as Nav1.6is expressed at high levels in dorsal root ganglia and can be found inspinal sensory tracts (Tzoumaka E, J. Neurosci. Res., 60(1): 37-44(2000)). It should be noted however that expression of Nav1.6 is notrestricted to sensory neurons of the periphery. Like the Nav1.6 channel,expression of the Nav1.3 VGSC can also be detected in both the centraland peripheral nervous system, though levels in the adult CNS aregenerally much higher than PNS. During development and the earlypostnatal period, Nav1.3 is expressed in peripheral neurons but thisexpression wanes as the animal matures (Shah B S, J. Physiol., 534(3):763-76 (2001); Schaller K L, Cerebellum, 2(1): 2-9 (2003)). Followingneuronal insult, Nav1.3 expression is upregulated, more closelymimicking the developmental expression patterns (Hains B C, J.Neurosci., 23(26): 8881-92 (2003)). Coincident with the recurrence ofNav1.3 expression is the emergence of a rapidly re-priming sodiumcurrent in the injured axons with a biophysical profile similar toNav1.3 (Leffler A, et al., J. Neurophysiol., 88(2): 650-8 (2002)).Treatment of injured axons with high levels of GDNF has been shown todiminish the rapidly repriming sodium current and reverse thermal andmechanical pain-related behaviors in a rat model of nerve injury,presumably by down-regulating the expression of Nav1.3 (Boucher T J,Curr. Opin. Pharmacol., 1(1): 66-72 (2001)). Specific down-regulation ofNav1.3 via treatment with antisense oligonucleotides has also been shownto reverse pain-related behaviors following spinal cord injury (Hains BC, J. Neurosci., 23(26): 8881-92 (2003)).

The Na_(v)1.7 (PN1, SCN9A) VGSC is sensitive to blocking by tetrodotoxinand is preferentially expressed in peripheral sympathetic and sensoryneurons. The SCN9A gene has been cloned from a number of species,including human, rat, and rabbit and shows ˜90% amino acid identitybetween the human and rat genes (Toledo-Aral et al., Proc. Natl. Acad.Sci. USA, 94(4): 1527-1532 (1997)).

An increasing body of evidence suggests that Na_(v)1.7 may play a keyrole in various pain states, including acute, inflammatory and/orneuropathic pain. Deletion of the SCN9A gene in nociceptive neurons ofmice led to a reduction in mechanical and thermal pain thresholds andreduction or abolition of inflammatory pain responses (Nassar et al.,Proc Natl Acad Sci USA, 101(34): 12706-11 (2004)). In humans, Na_(v)1.7protein has been shown to accumulate in neuromas, particularly painfulneuromas (Kretschmer et al., Acta. Neurochir. (Wien), 144(8): 803-10(2002)). Gain of function mutations of Na_(v)1.7, both familial andsporadic, have been linked to primary erythermalgia, a diseasecharacterized by burning pain and inflammation of the extremities (Yanget al., J. Med. Genet., 41(3): 171-4 (2004), and paroxysmal extreme paindisorder (Waxman, S G Neurology. 7; 69(6): 505-7 (2007)). Congruent withthis observation is the report that the non-selective sodium channelblockers lidocaine and mexiletine can provide symptomatic relief incases of familial erythermalgia (Legroux-Crepel et al., Ann. DermatolVenereol., 130: 429-433) and carbamazepine is effective in reducing thenumber and severity of attacks in PEPD (Fertleman et al, Neuron.;52(5):767-74 (2006). Further evidence of the role of Nav1.7 in pain isfound in the phenotype of loss of function mutations of the SCN9A gene.Cox and colleagues (Nature, 444(7121):894-8 (2006)) were the first toreport an association between loss-of-function mutations of SNC9A andcongenital indifference to pain (CIP), a rare autosomal recessivedisorder characterized by a complete indifference or insensitivity topainful stimuli. Subsequent studies have revealed a number of differentmutations that result in a loss of function of the SCN9A gene and theCIP phenotype (Goldberg et al, Clin Genet.; 71(4): 311-9 (2007), Ahmadet al, Hum Mol. Genet. 1; 16(17): 2114-21 (2007)).

Sodium channel-blocking agents have been reported to be effective in thetreatment of various disease states, and have found particular use aslocal anesthetics and in the treatment of cardiac arrhythmias. It hasalso been reported that sodium channel-blocking agents may be useful inthe treatment of pain, including acute, chronic, inflammatory and/orneuropathic pain; see, for example, Wood, J N et al., J. Neurobiol.,61(1): 55-71 (2004). Preclinical evidence demonstrates that sodiumchannel-blocking agents can suppress neuronal firing in peripheral andcentral sensory neurons, and, it is via this mechanism, that they may beuseful for relieving pain. In some instances, abnormal or ectopic firingcan originate from injured or otherwise sensitized neurons. For example,it has been shown that sodium channels can accumulate in peripheralnerves at sites of axonal injury and may function as generators ofectopic firing (Devor et al. J. Neurosci., 132: 1976 (1993)). Changes insodium channel expression and excitability have also been shown inanimal models of inflammatory pain where treatment with proinflammatorymaterials (CFA, Carrageenan) promoted pain-related behaviors andcorrelated with increased expression of sodium channel subunits (Gouldet al., Brain Res., 824(2): 296-9 (1999); Black et al., Pain, 108(3):237-47 (2004)). Alterations in either the level of, expression of, ordistribution of sodium channels, therefore, may have a major influenceon neuronal excitability and pain-related behaviors. As such there is adesire to seek new sodium channel modulators.

WO-A-2005/054176 discusses peroxisome proliferator activated receptormodulators.

EP-A-1088819 discusses 6-azauracil derivatives, which are stated to bethyroid receptor ligands.

International patent application WO-A-2005/013914 (publication date 17Feb. 2005) discloses compounds, in particular heteroarylaminosulfonylphenyl derivatives, which are useful as inhibitors of voltagegated sodium channels with a number of therapeutic uses, including thetreatment of pain.

International patent application WO-A-2008/118758 (publication date 2Oct. 2008) discloses compounds, in particular aryl sulphonamides, whichare sodium channel modulators with a number of therapeutic uses,particularly for the treatment of pain.

International patent application WO-A-2009/012242 (publication date 22Jan. 2009) discloses compounds, in particular N-thiazolylbenzenesulfonamides, which are sodium channel modulators with a numberof therapeutic uses, particularly for the treatment of pain.

However, there remains a need for still further new sodium channelmodulators, including modulators which are potentially able to blockactivity at a given sodium channel. The compounds of the presentinvention described herein are selective Nav1.7 channel modulators. Inparticular, they show an affinity for the Nav1.7 channel which isgreater than their affinity for Nav1.5 channels. Preferred compounds ofthe invention show selectivity for the Nav1.7 channel as compared withthe Nav1.5. Advantageously, the compounds of the invention show littleor no affinity for the Nav1.5 channel.

The compounds of the present invention, being Nav 1.7 modulators, aretherefore potentially useful in the treatment of a wide range ofdisorders, particularly pain. The treatment of pain is a preferred use.All forms of pain are potentially treatable with the compounds of thepresent invention including acute pain; chronic pain; neuropathic pain;inflammatory pain; visceral pain; nociceptive pain includingpost-surgical pain; and mixed pain types involving the viscera,gastrointestinal tract, cranial structures, musculoskeletal system,spine, urogenital system, cardiovascular system and CNS, includingcancer pain, back and orofacial pain.

Other conditions that may be treated with the compounds of the presentinvention include anal fissure, neuronal injury, spinal injury andepilepsy.

It is an objective of the invention to provide new Nav1.7 channelmodulators and that, preferably, such new modulators are suitable forfurther development as drug candidates. Preferred compounds should bindpotently to the Nav1.7 channel, show functional activity as Nav1.7channel modulators, and preferably show little affinity for other sodiumchannels, particularly Nav1.5. Furthermore, the preferred compoundsshould have one or more of the following improved properties: be wellabsorbed from the gastrointestinal tract; be metabolically stable; havean improved metabolic profile, in particular with respect to thetoxicity or allergenicity of any metabolites formed; or possessfavourable pharmacokinetic properties whilst still retaining theiractivity profile as Nav1.7 channel modulators. It is further preferredthat they should also be non-toxic and demonstrate few side-effects.Furthermore, such preferred drug candidates should preferably exist in aphysical form that is stable, non-hygroscopic and easily formulated.Preferred compounds of the present invention are selective for theNav1.7 channel over Nav1.5, which may potentially lead to one or moreimprovements in the side-effect profile. Without wishing to be bound bytheory, such selectivity, is thought to advantageously reduce anycardiovascular side effects which may be associated with affinity forthe Nav1.5 channel. Preferably compounds of the present inventiondemonstrate a selectivity of 10-fold, more preferably 30-fold, mostpreferably 100-fold, for the Nav 1.7 channel when compared to theirselectivity for the Nav1.5 channel whilst maintaining good potency forthe Nav1.7 channel. In addition, the most preferred compounds of thepresent invention may optionally also show selectivity for the Nav1.7channel over Nav1.3, whilst maintaining good potency for the Nav1.7channel.

SUMMARY OF THE INVENTION

The invention therefore provides as Embodiment 1 a compound of theformula (I):

wherein

Z is Het², optionally substituted on a ring carbon atom with one or moresubstituents selected from the group consisting of halo, cyano,(C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₄)alkyl, (C₁-C₄)alkyl-S—,amino, (C₁-C₄)alkylamino, di(C₁-C₄)alkylamino, amino(C₁-C₄)alkyl,(C₁-C₄)alkylamino(C₁-C₄)alkyl, and di[(C₁-C₄)alkyl]amino(C₁-C₄)alkyl;and/or Het² is optionally substituted on a ring nitrogen atom with(C₁-C₄)alkyl, halo(C₁-C₄)alkyl and (C₃-C₈)cycloalkyl; with the provisothat Z is not tetrazolyl;

Y¹, Y², Y³ and Y⁴ are each independently CH, CR¹ or N, provided that nomore than two of Y¹, Y², Y³ and Y⁴ are N;

each R¹ is independently selected from the group consisting of halo,cyano, amino, hydroxy, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,(C₁-C₄)alkoxy(C₁-C₄)alkyl, —C(O)H, —C(O)(C₁-C₄)alkyl, and —C(O)N(R²)₂;

each R² is independently hydrogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,hydroxy(C₁-C₄)alkyl, or (C₃-C₆)cycloalkyl; or, where a nitrogen issubstituted with two R² groups, each independently selected from(C₁-C₄)alkyl, halo(C₁-C₄)alkyl, or hydroxy(C₁-C₄)alkyl, they may betaken together with the N atom to which they are attached to form a 4-to 6-membered ring which, when so formed, may therefore optionally besubstituted with hydrogen, alkyl, halo, hydroxy, hydroxyalkyl orhaloalkyl;

B is phenyl or Het², wherein, when B is Het² it is attached to the oxylinker at a ring carbon atom, and wherein B is optionally furthersubstituted on a ring carbon atom with one or more substituents selectedfrom the group consisting of halo, cyano, hydroxy, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, cyano(C₁-C₄)alkyl,amino, (C₁-C₄)alkylamino, di(C₁-C₄)alkylamino, amino(C₁-C₄)alkyl,(C₁-C₄)alkylamino(C₁-C₄)alkyl, di[(C₁-C₄)alkyl]amino(C₁-C₄)alkyl,trifluoromethylthio, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl,—C(O)R², —C(O)OR², —OC(O)R², —C(O)—N(R²)₂, —CH₂—C(O)R², —CH₂—C(O)OR²,—CH₂—OC(O)R², —CH₂—C(O)—N(R²)₂, S(O)₂R², S(O)₂N(R²)₂, (C₃-C₈)cycloalkyl,and (C₃-C₈)cycloalkyl(C₁-C₄)alkyl; and/or

Het² is optionally substituted on a ring nitrogen atom with asubstituent selected from the group consisting of (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl,amino(C₁-C₄)alkyl, (C₁-C₄)alkylamino(C₁-C₄)alkyl,di[(C₁-C₄)alkyl]amino(C₁-C₄)alkyl, —CH₂—C(O)R², —CH₂—C(O)OR²,—CH₂—C(O)—N(R²)₂, S(O)₂R², and S(O)₂N(R²)₂;

X is absent, —O—, methylene, ethylene, methylene-O—, or —O-methylene;

C is (C₃-C₈)cycloalkyl, Het¹, phenyl, or Het², each optionallysubstituted on a ring carbon atom with one or more substituents selectedfrom the group consisting of halo, cyano, hydroxy, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, N(R²)₂,(R²)₂N(C₁-C₄)alkyl, trifluoromethylthio, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkoxy(C₁-C₄)alkyl, —C(O)R², —C(O)OR², —OC(O)R², —C(O)—N(R²)₂,—CH₂—C(O)R², —CH₂—C(O)OR², —CH₂—OC(O)R², —CH₂—C(O)—N(R²)₂, S(O)₂R²,S(O)₂N(R²)₂, (C₃-C₈)cycloalkyl(C₁-C₄)alkyl, (C₃-C₈)cycloalkoxy,(C₃-C₈)cycloalkylamino, (C₃-C₈)cycloalkylamino(C₁-C₄)alkyl,(C₃-C₈)cycloalkyl(C₁-C₄)alkylamino,(C₃-C₈)cycloalkyl(C₁-C₄)alkylamino(C₁-C₄)alkyl,(C₃-C₈)cycloalkyl(C₁-C₄)alkoxy and D; and/or

Het² is optionally substituted on a ring nitrogen atom with asubstituent selected from the group consisting of hydroxy, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, amino(C₁-C₄)alkyl, (C₁-C₄)alkylamino(C₁-C₄)alkyl,di[(C₁-C₄)alkyl]amino(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkoxy(C₁-C₄)alkyl, —C(O)R², —C(O)OR², —CH₂—C(O)R², —CH₂—C(O)OR²,—CH₂—C(O)—N(R²)₂, S(O)₂R², and S(O)₂N(R²)₂ and D;

with the proviso that C is not3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl;

D is phenyl, benzyl, (C₃-C₈)cycloalkyl, or Het¹, each optionallysubstituted on a carbon atom with one or more substituents independentlyselected from the group consisting of halo, cyano, hydroxy,(C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, amino,(C₁-C₄)alkylamino, di(C₁-C₄)alkylamino, amino(C₁-C₄)alkyl,(C₁-C₄)alkylamino(C₁-C₄)alkyl, di[(C₁-C₄)alkyl]amino(C₁-C₄)alkyl,trifluoromethylthio, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl,—C(O)R², —C(O)OR², —OC(O)R², —C(O)—N(R²)₂, —CH₂—C(O)R², —CH₂—C(O)OR²,—CH₂—OC(O)R², —CH₂—C(O)—N(R²)₂, S(O)₂R², and S(O)₂N(R²)₂;

Het¹ is a 3- to 8-membered, saturated or partially unsaturatedmonocyclic heterocyclic group comprising one or two or three ringmembers selected from —NR³—, —O—, —C(O)— and —S(O)_(p)—;

R³ is either the point of attachment to X or C to give

or R³ is selected from the group consisting of hydrogen, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl,—C(O)(C₁-C₄)alkyl, —C(O)O(C₁-C₄)alkyl, —CH₂—C(O)O(C₁-C₄)alkyl,—CH₂—C(O)—N((C₁-C₄)alkyl)₂, S(O)₂R², S(O)₂N(R²)₂ and (C₃-C₈)cycloalkyl;

p is 0, 1 or 2; and

Het² is a 5- or 6-membered aromatic heterocyclic group comprising either(a) 1 to 4 nitrogen atoms, (b) one oxygen or one sulphur atom or (c) 1oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms;

or a tautomer thereof, or a pharmaceutically acceptable salt or solvateof the compound of formula (I), or its tautomer;

with the proviso that the compound of formula (I) is not the followingspecific compound:

As used herein the term alkyl means an alicyclic, saturated hydrocarbonchain of the formula C_(n)H_(2n+1) containing the requisite number ofcarbon atoms, which may be linear or branched. Examples of such groupsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isoamyl and hexyl. Unless other wisespecified the alkyl group contains from 1 to 6 carbon atoms.

As used herein the term alkylene means a bivalent acyclic, saturatedhydrocarbon group of the formula C_(n)H_(2n) containing the requisitenumber of carbon atoms, which may be linear or brached. Examples ofalkylene include methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene,1,2-propylene, 1,3-propylene and 2,2-propylene. Unless otherwisespecified the alkylene group contains from 1 to 6 carbon atoms.

As used herein the term aryl means a phenyl ring or a 5- or 6-memberedaromatic heterocyclic group both of which can be optionally substitutedwith one or more substituents selected from the group consisting ofhalo, CN, halo(C₁-C₄)alkyl, halo(C₁-C₄)alkoxy, and NO₂.

As used herein the term halo means fluoro, chloro, bromo or iodo.

As used herein the term alkoxy means an alicyclic, saturated hydrocarbonchain of the formula OC_(n)H_(2n+1) containing the requisite number ofcarbon atoms, which may be linear or branched. Examples of alkoxyinclude methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,sec-butoxy and t-butoxy.

Haloalkyl and haloalkoxy mean an alkyl or alkoxy group, containing therequisite number of carbon atoms, substituted with one or more haloatoms as hereinbefore defined.

The term “hydroxy” as used herein means an OH group.

Specific examples of cycloalkyl include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl, preferably cyclopropyl,cyclobutyl, cyclopentyl or cyclohexyl each of which may be optionallysubstituted as specified.

Specific examples of Het¹ include oxiranyl, aziridinyl, oxetanyl,azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepinyl,oxapinyl, oxazepinyl and diazepinyl (each optionally substituted asspecified above).

Specific examples of Het² include pyrrolyl, furanyl, thiophenyl,pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl,triazolyl oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl,pyrimidinyl, and pyrazinyl (optionally substituted as specified above).The structures of these groups are depicted below:

In the following embodiments of the invention, any group notspecifically defined has the same meaning as given for formula (I)above. In each case, where an embodiment covers a compound where:

-   -   Z is tetrazolyl;    -   C is 3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl; or    -   a compound of formula

such compounds are excluded.

In Embodiment (2), the invention provides a compound of formula (I), ora pharmaceutically acceptable salt, solvate or tautomer thereof,according to Embodiment 1, wherein Z is Het², optionally substituted asdefined in Embodiment 1, with the proviso that Z is not tetrazolyl.

In Embodiment (2a), the invention provides a compound of formula (I), ora pharmaceutically acceptable salt, solvate or tautomer thereof,according to Embodiment 1, wherein Z is Het², optionally substituted asdefined in Embodiment 1, with the proviso that Z is not tetrazolyl orisoxazoyl.

In Embodiment (2.1), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to Embodiment 1, wherein Z is a 5-membered aromaticheterocyclic group comprising either thiophenyl, or comprises either (a)1 to 3 nitrogen atoms or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2nitrogen atoms, and Z is optionally substituted as defined in Embodiment1.

In Embodiment (2.2), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to Embodiment 1, wherein Z is thiophenyl, imidazolyl,isothiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,1-thia-3,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-2,4-diazolyl,1-thia-2,3-diazolyl, 1,3,4-triazolyl, oxazolyl, pyrazolyl,1-oxa-2,5-diazolyl, or isoxazolyl, and Z is optionally substituted asdefined in Embodiment 1.

In Embodiment (2.2a), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to Embodiment 1, wherein Z is imidazolyl, isothiazolyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 1-thia-3,4-diazolyl,1-thia-2,5-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,3-diazolyl,1,3,4-triazolyl, oxazolyl and Z is optionally substituted as defined inEmbodiment 1.

In Embodiment (2.2b), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to Embodiment 1, wherein Z is 2-thiazolyl, 4-thiazolyl,1-thia-3,4-diazolyl or 1-thia-2,4-diazolyl and Z is optionallysubstituted as defined in Embodiment 1.

In Embodiment (2.2c), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to Embodiment 1, wherein Z is thiophenyl, imidazolyl,isothiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,1-thia-3,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-2,4-diazolyl,1-thia-2,3-diazolyl, 1,3,4-triazolyl, oxazolyl, pyrazolyl,1-oxa-2,5-diazolyl, or isoxazolyl, and Z is either unsubstituted oroptionally substituted on a ring carbon atom with halo, for examplebromo, chloro, fluoro or iodio; (C₁-C₄)alkyl, for example methyl, ethylor isopropyl; (C₁-C₄)alkoxy, for example methoxy or ethoxy;(C₁-C₄)alkyl-S—, for example CH₃S—; or cyano; or optionally substitutedon a ring nitrogen atom with (C₁-C₄)alkyl, for example methyl.

In Embodiment (2.3), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to Embodiment 1, wherein Z is either 2-thiazolyl or4-thiazolyl each of which are either unsubstituted or monosubstituted ona ring carbon atom with halo, for example chloro; or Z is1-thia-3,4-diazolyl which is unsubstituted; or Z is 1-thia-2,4-diazolylwhich is unsubstituted.

In an alternative Embodiment (2.4), the invention provides a compound offormula (I), or a pharmaceutically acceptable salt, solvate or tautomerthereof, according to Embodiment 1, wherein Z is 6-membered aromaticheterocyclic group comprising 1 to 4 nitrogen atoms, and Z is optionallysubstituted as defined in Embodiment 1.

In Embodiment (2.5), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to Embodiment 1, wherein Z is pyridinyl, pyrazinyl,pyridazinyl, or pyrimidinyl, more preferably pyridinyl, pyridazinyl, orpyrimidinyl and Z is optionally substituted as defined in Embodiment 1.

In Embodiment (2.5a), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to Embodiment 1, wherein Z is pyridinyl, pyrazinyl,pyridazinyl, or pyrimidinyl and Z is optionally substituted on a ringcarbon atom with halo, for example chloro, or fluoro; (C₁-C₄)alkyl, forexample methyl; halo(C₁-C₄)alkyl, for example trifluoromethyl;(C₁-C₄)alkoxy, for example methoxy; or cyano.

In Embodiment (2.6) the invention provides a compound of formula (I), ora pharmaceutically acceptable salt, solvate or tautomer thereof,according to Embodiment 1, wherein Z is pyrimidinyl, which isunsubstituted; or Z is pyridinyl which is substituted on a ring carbonwith halo, for example fluoro; or Z is pyridazinyl, which isunsubstituted.

In another Embodiment (2.7), the invention provides a compound offormula (I), or a pharmaceutically acceptable salt, solvate or tautomerthereof, according to Embodiment 1, wherein Z is Het² substituted on aring nitrogen as defined in Embodiment 1. Preferably Z is imidazolylsubstituted on a ring nitrogen, more preferably substituted on a ringnitrogen with (C₁-C₄)alkyl, for example methyl.

In Embodiment (3), the invention provides a compound of formula (I), ora pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein Y² and Y³ cannot both beN; more preferably, no more than one of Y¹, Y², Y³ and Y⁴ is N.

In Embodiment (3.1), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein

Y¹ is N, Y² is CR¹, and Y³ and Y⁴ are each CH; or

Y¹ is N, Y⁴ is CR¹, and Y² and Y³ are each CH; or

Y¹, Y², Y³ and Y⁴ are each independently CH or CR¹, where preferably nomore than two of Y¹, Y², Y³ and Y⁴ are CR¹.

In Embodiment (3.2), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein

Y¹, Y², Y³ and Y⁴ are each CH; or

Y¹ is CR¹, and Y², Y³ and Y⁴ are each CH; or

Y² is CR¹ and Y¹, Y³ and Y⁴ are each CH; or

Y¹ and Y⁴ are CR¹ and Y² and Y³ are CH; or

Y¹ and Y³ are CR¹ and Y² and Y⁴ are CH; or

Y¹ and Y² are CR¹ and Y³ and Y⁴ are CH.

In Embodiment (3.3), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein

Y¹ is CR¹, and Y², Y³ and Y⁴ are each CH; or

Y¹ and Y³ are CR¹ and Y² and Y⁴ are CH.

In Embodiment (4), the invention provides a compound of formula (I), ora pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein each R¹ is independentlyselected from the group consisting of halo, cyano, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, —C(O)H, NH₂ and —C(O)NH₂; morepreferably, each R¹ is independently selected from the group consistingof fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, trifluoromethyl,methoxy, —C(O)H, NH₂ and —C(O)NH₂.

In Embodiment (4.1), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein Y¹ is N, Y⁴ is CR¹, andY² and Y³ are each CH and R¹ is independently selected from halo, forexample chloro; or cyano.

In Embodiment (4.2), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein one of Y¹, Y², Y³ or Y⁴are CR¹, and the others are each CH, and R¹ is independently selectedfrom halo, for example fluoro, chloro or iodo; cyano; (C₁-C₄)alkyl, forexample methyl or ethyl; halo(C₁-C₄)alkyl, for example trifluoromethyl;(C₁-C₄)alkoxy, for example methoxy; and —C(O)NH₂.

In yet another alternative preferred embodiment (4.3), the inventionprovides a compound of formula (I), or a pharmaceutically acceptablesalt, solvate or tautomer thereof, according to any precedingEmbodiment, wherein Y¹ is CR¹, and Y², Y³ and Y⁴ are each CH and R¹ iscyano.

In yet another alternative preferred embodiment (4.4), the inventionprovides a compound of formula (I), or a pharmaceutically acceptablesalt, solvate or tautomer thereof, according to any precedingEmbodiment, wherein two of Y¹ Y², Y³ and Y⁴ are CR¹ and the other twoare CH and each R¹ is independently selected from halo, for examplefluoro, chloro or bromo; cyano; and (C₁-C₄)alkyl, for example methyl.

In Embodiment (4.5), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein Y¹ and Y³ are CR¹ and Y²and Y⁴ are CH and each R¹ is independently selected from halo, forexample fluoro or chloro; or (C₁-C₄)alkyl, for example methyl. Forexample, both R¹ groups are fluoro. Alternatively one is fluoro and theother chloro. Yet another alternative is where one R¹ group is fluoroand the other R¹ group is methyl.

In Embodiment (5), the invention provides a compound of formula (I), ora pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein B is selected from thegroup consisting of:

(i) phenyl;

(ii) 5-membered aromatic heterocyclic group comprising either (a) 1 to 3nitrogen atoms, or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2nitrogen atoms;

(iii) 6-membered aromatic heterocyclic group comprising 1 or 2 nitrogenatoms;

and wherein B is optionally substituted as defined in Embodiment 1.

In Embodiment (5a), the invention provides a compound of formula (I), ora pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein B is phenyl optionallysubstituted as defined in Embodiment 1.

In Embodiment (5b), the invention provides a compound of formula (I), ora pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein B is a 5-memberedaromatic heterocyclic group comprising either (a) 1 to 3 nitrogen atoms,or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms, morepreferably where B is a 5-membered aromatic heterocyclic groupcomprising either (a) 1 to 3 nitrogen atoms, or (c) 1 oxygen atom or 1sulphur atom and 1 or 2 nitrogen atoms but is not pyrazolyl, optionallysubstituted as defined in Embodiment 1.

In Embodiment (5c), the invention provides a compound of formula (I), ora pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein B is a 6-memberedaromatic heterocyclic group comprising 1 or 2 nitrogen atoms optionallysubstituted as defined in Embodiment 1.

In Embodiment (5.1), the invention provides a compound of the formula(I), or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein B is phenyl, thiazolyl,thiadiazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinylor pyrazinyl, and wherein B is optionally substituted as defined inEmbodiment 1.

In Embodiment (5.1a), the invention provides a compound of the formula(I), or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein B is phenyl, thiazolyl,thiadiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl orpyrazinyl, and wherein B is optionally substituted as defined inEmbodiment 1.

In a most preferred Embodiment (5.2), the invention provides a compoundof the formula (I), or a pharmaceutically acceptable salt, solvate ortautomer thereof, according to any preceding Embodiment, wherein B isphenyl, optionally substituted as defined in Embodiment 1.

In Embodiment (5.3), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein B is unsubstituted; or

is substituted on a ring carbon atom with one or two substituentsindependently selected from the group consisting of halo, cyano,(C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,cyano(C₁-C₄)alkyl, amino, (C₁-C₄)alkylamino, di(C₁-C₄)alkylamino,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, —C(O)OR², —C(O)—N(R²)₂,—CH₂—C(O)—N(R²)₂ and (C₃-C₈)cycloalkyl; and/or

is substituted on a ring nitrogen atom with one or two substituentsindependently selected from the group consisting of (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, CH₂—C(O)R², or —CH₂C(O)OR².

In Embodiment (5.4), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein B is unsubstituted; or

is substituted on a ring carbon atom with one or two substituentsselected from cyano, methyl, ethyl, i-propyl, i-butyl, t-butyl,trifluoromethyl, 2,2,2-trifluoroethyl, C(CH₃)₂CN, methoxy,difluoromethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl,hydroxypropyl, hydroxybutyl, methoxymethyl, bromo, chloro, fluoro, iodo,—NH₂, —NH(CH₃), —N(CH₃)₂, —CH₂—C(O)—NH₂, —C(O)—N(CH₃)₂, —C(O)OCH₃ andcyclopropyl; and/or

is substituted on a ring nitrogen atom with one or two substituentsselected from methyl, t-butyl, hydroxyethyl, —CH₂C(O)H,—CH₂—C(O)O—CH₂CH₃ or 2,2,2-trifluoroethyl.

In Embodiment (5.5), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein B is phenyl, which isunsubstituted; or

is substituted on a ring carbon with one substituent selected from halo,for example fluoro, chloro, bromo, or iodo; cyano; (C₁-C₄)alkyl, forexample methyl, ethyl, i-propyl, or i-butyl; halo(C₁-C₄)alkyl, forexample trifluoromethyl; (C₁-C₄)alkoxy, for example methoxy;cyano(C₁-C₄)alkyl, for example C(CH₃)₂CN; halo(C₁-C₄)alkoxy, for exampledifluoromethoxy, or trifluoromethoxy; hydroxy(C₁-C₄)alkyl, for examplehydroxymethyl, hydroxyethyl, hydroxypropyl, or hydroxybutyl;(C₁-C₄)alkoxy(C₁-C₄)alkyl, for example methoxymethyl; —C(O)OR², forexample when R² is (C₁-C₄)alkyl, for example methyl, to form —C(O)OCH₃;—C(O)—N(R²)₂ for example when R² is (C₁-C₄)alkyl, for example methyl, toform —C(O)—N(CH₃)₂; and (C₃-C₈)cycloalkyl, for example cyclopropyl; or

is substituted on a ring carbon with two substituents independentlyselected from halo, for example fluoro, chloro or bromo; and(C₁-C₄)alkyl, for example methyl, to form, for example difluoro;dichloro; dibromo; fluoro, chloro; or chloro, methyl.

In Embodiment (5.6) the invention provides a compound of formula (I), ora pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein B is phenyl, which issubstituted on a ring carbon with one substituent selected from halo,for example fluoro, or chloro; halo(C₁-C₄)alkyl, for exampletrifluoromethyl; or halo(C₁-C₄)alkoxy, trifluoromethoxy; or

is substituted on a ring carbon with two substituents, selected fromhalo, for example fluoro, or chloro; halo(C₁-C₄)alkyl, for exampletrifluoromethyl; or halo(C₁-C₄)alkoxy, trifluoromethoxy. For example onesubstituent is fluoro and the other chloro. Alternatively onesubstituent is fluoro and the other is trifluoromethyl.

In a preferred Embodiment (6), the invention provides a compound offormula (I), or a pharmaceutically acceptable salt, solvate or tautomerthereof, according to any preceding Embodiment, wherein C is(C₃-C₈)cycloalkyl, for example cyclopropyl or cyclohexyl, optionallysubstituted as defined in Embodiment 1.

In Embodiment (6a), the invention provides a compound of formula (I), ora pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein the C ring, at the atomwhere it attaches to X, or directly to ring B if X is absent, is notfurther substituted except that such an atom may be substituted byhydrogen if chemically possible.

In Embodiment (6b), the invention provides a compound of formula (I), ora pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein C is phenyl, optionallysubstituted as defined in Embodiment 1.

In Embodiment (6c), the invention provides a compound of formula (I), ora pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein C is Het¹, optionallysubstituted as defined in Embodiment 1.

In Embodiment (6d), the invention provides a compound of formula (I), ora pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein C is Het², optionallysubstituted as defined in Embodiment 1.

In Embodiment (6.1), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein C is Het², attached to X,or directly to ring B if X is absent, at a carbon atom and optionallysubstituted as defined in Embodiment 1.

In Embodiment (6.1a), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein C is Het¹, attached to X,or directly to ring B if X is absent, at a carbon atom and optionallysubstituted as defined in Embodiment 1.

In Embodiment (6.2), the invention provides a compound of the formula(I), or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein C is a 5-memberedaromatic heterocyclic group comprising either (a) 1 to 4 nitrogen atoms,(b) one oxygen or one sulphur atom or (c) 1 oxygen atom or 1 sulphuratom and 1 or 2 nitrogen atoms, for example furanyl, pyrazolyl;imidazolyl; 1,2,3-triazolyl; 1,3,4-triazolyl; tetrazolyl; thiazolyl;isothiazolyl; oxazolyl; isoxazolyl; or 1-oxa-2,4-diazolyl, eachoptionally substituted as defined in Embodiment 1.

In another even more preferred Embodiment (6.2a), the invention providesa compound of the formula (I), or a pharmaceutically acceptable salt,solvate or tautomer thereof, according to any preceding Embodiment,wherein C is a 6-membered aromatic heterocyclic group comprising either(a) 1 to 4 nitrogen atoms, (b) one oxygen or one sulphur atom or (c) 1oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms, for examplepyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each optionallysubstituted as defined in Embodiment 1.

In yet another even more preferred Embodiment (6.2b), the inventionprovides a compound of the formula (I), or a pharmaceutically acceptablesalt, solvate or tautomer thereof, according to any precedingEmbodiment, wherein C is a 3- to 8-membered, saturated or partiallyunsaturated monocyclic heterocyclic group comprising one or two ringmembers selected from —NR³—, —O—, —C(O)—, for example azetidinyl;pyrrolidinyl; piperidinyl; oxetanyl; tetrahydropyranyl; pyrrolidonyl;imidazolidonyl; or morpholinyl, each optionally substituted as definedin Embodiment 1.

In yet further preferred Embodiment (6.3) the invention provides acompound of the formula (I), or a pharmaceutically acceptable salt,solvate or tautomer thereof, according to any preceding Embodiment,wherein C is phenyl; cyclopropyl; cyclohexyl; pyrazolyl; furanyl,imidazolyl; 1,2,3-triazolyl; 1,2,4-triazolyl; 1,3,4-triazolyl;tetrazolyl; thiazolyl; isothiazolyl; oxazolyl; isoxazolyl;1-oxa-2,4-diazolyl; pyridinyl; pyrazinyl; pyridazinyl; pyrimidinyl;azetidinyl; pyrrolidinyl; piperidinyl; oxetanyl; tetrahydropyranyl;pyrrolidonyl; imidazolidonyl; or morpholinyl, each optionallysubstituted as defined in Embodiment 1.

In Embodiment (6.3a), the invention provides a compound of the formula(I), or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein C is pyrazolyl;pyridinyl; pyridazinyl; pyrimidinyl; azetidinyl; piperidinyl; ortetrahydropyranyl; each optionally substituted as defined in Embodiment1.

In Embodiment (6.4) the invention provides a compound of the formula(I), or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein C is unsubstituted; or

C is substituted on a ring carbon atom with one or two substituentsselected from the group consisting of halo, cyano, hydroxy,(C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,(R²)₂-amino, (R²)₂-amino(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkoxy(C₁-C₄)alkyl, —C(O)R², —CH₂—O—C(O)R², —C(O)—NH₂,—C(O)—N(R²)₂, (C₃-C₈)cycloalkoxy, and D; and/or

when C is Het² it is substituted on a ring nitrogen atom with onesubstituent selected from the group consisting of (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, di[(C₁-C₄)alkyl]amino(C₁-C₄)alkyl,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, —C(O)R². —CH₂—C(O)O—R₂,—CH₂—C(O)—NR₂; and D; and/or

-   -   when C is Het¹, R³ is optionally selected from the group of        substituents consisting of hydrogen, (C₁-C₄)alkyl, or        —C(O)(C₁-C₄)alkyl.

In Embodiment (6.5) the invention provides a compound of the formula(I), or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein C is unsubstituted; or

C is substituted on a ring carbon atom with one or two substituentsselected from the group consisting of chloro, fluoro, cyano, hydroxy,methyl, ethyl, i-proyl, t-butyl, difluoromethyl, trifluoromethyl,methoxy, ethoxy, i-propoxy, trifluoromethoxy, NH₂, —N(CH₃)₂, —CH₂NH₂,—NH(cyclobutyl), —CH₂N-azetidinyl, —CH₂N-3,3-difluoroazetidinyl,—CH₂N-3,3-dihydroxymethylazetidinyl, —CH₂N-3-hydroxypyrrolidinylhydroxymethyl, hydroxyethyl, methoxymethyl, -methoxyethyl, —C(O)CH₃,—C(O)OH, —CH₂C(O)OCH₃, —CH₂OC(O)CF₃, —C(O)—NH₂, —C(O)—N(CH₃)₂,—C(O)—NH(t-butyl), C(O)—NH(cyclopropyl), —C(O)N-azetidinyl,—C(O)N-3-methylazetidinyl cyclobutyloxy, and D, wherein D iscyclopropyl, cyclohexyl, azetidinyl, morpholinyl and piperazinyl; and/or

when C is Het², it is substituted on a ring nitrogen atom with onesubstituent selected from the group consisting of hydroxy, methyl,ethyl, t-butyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,3-fluoropropyl, (CH₂)₂N(CH₃)₂, hydroxyethyl, methoxyethyl, —C(O)CH₃,—CH₂—C(O)O—CH₂CH₃, —CH₂—C(O)OH, —CH₂—C(O)—N(CH₃)₂ and D, wherein D isphenyl, benzyl, cyclopropyl, cyclobutyl, dioxidotetrahydro-3-thienyl,azetidinyl, N-methylazetidinyl, N-ethylazetidinyl,N-isopropylazetidinyl, tetrahydrafuranyl, piperidinyl,N-methylpiperidinyl; and/or

when C is Het¹, R³ is either the point of attachment to X; hydrogen,methyl or C(O)CH₃, C(O)OCH₃, C(O)OC(CH₃)₃.

In an even more preferred Embodiment (6.6), invention provides acompound of formula (I), or a pharmaceutically acceptable salt, solvateor tautomer thereof, according to any preceding Embodiment, wherein C ispyrazolyl, which is preferably attached to X, or directly to ring B if Xis absent, via a carbon atom, more preferably via the carbon at the 3position or the carbon at the 4 position and most preferably via thecarbon at the 3 position.

In Embodiment (6.6a), invention provides a compound of formula (I), or apharmaceutically acceptable salt, solvate or tautomer thereof, accordingto any preceding Embodiment, wherein C is pyrazolyl, which isunsubstituted, or

which is substituted on a ring carbon atom with one or two substituentsindependently selected from halo, for example fluoro, chloro; cyano;hydroxy; (C₁-C₄)alkyl, for example methyl; halo(C₁-C₄)alkyl, for exampledifluoromethyl or trifluoromethyl; (C₁-C₄)alkoxy, for example methoxy,ethoxy, i-propoxy, methoxymethy, or methoxyethyl; amino;di(C₁-C₄)alkylamino, for example N(CH₃)₂; hydroxy(C₁-C₄)alkyl, forexample hydroxymethyl; —C(O)OR², wherein R² is (C₁-C₄)alkyl, for exampleethyl; —CH₂—O—C(O)R² wherein R² is independently selected fromhalo(C₁-C₄)alkyl, for example trifluoromethyl; —C(O)—N(R²)₂ wherein R²is independently selected from hydrogen, or (C₁-C₄)alkyl, for examplemethyl or t-butyl; and D, wherein D is (C₃-C₈)cycloalkyl, for examplecyclopropyl, which is unsubstituted; and/or

which is substituted on a ring nitrogen atom with one substituentselected from (C₁-C₄)alkyl, for example methyl, ethyl or t-butyl;halo(C₁-C₄)alkyl, for example difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, or 3,3,3-trifluoropropyl;(C₁-C₄)alkoxy(C₁-C₄)alkyl, for example methoxyethyl;di[(C₁-C₄)alkyl]amino(C₁-C₄)alkyl, for example (CH₂)₂N(CH₃)₂; —C(O)R²,wherein R² is (C₁-C₄)alkyl, for example t-butyl; —CH₂—C(O)OR² wherein R²is independently selected from hydrogen, or (C₁-C₄)alkyl, for exampleethyl; —CH₂—C(O)—N(R²)₂, wherein both R² are selected from hydrogen, or(C₁-C₄)alkyl, for example methyl; and D, for example phenyl, which isunsubstituted; benzyl, which is unsubstituted; (C₃-C₈)cycloalkyl, forexample cyclopropyl or cyclobutyl; Het¹, for example azetidinyl which isattached to the C ring via a carbon atom, more preferably via a carbonatom at the 3 position and which azetidinyl is unsubstituted, or whichis substituted on the N atom with (C₁-C₄)alkyl, for example methyl,ethyl or isopropyl, or C(O)(C₁-C₄)alkyl, for example C(O)CH₃; orpiperidinyl which is unsubstituted, or which is substituted on the Natom with (C₁-C₄)alkyl, for example methyl; ordioxidotetrahydro-3-thienyl which is unsubstituted; ortetrahydrofuranyl, which is unsubstituted.

In Embodiment (6.7), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein C is pyrazolyl, which isunsubstituted, or which is substituted on a ring carbon atom with onesubstituent selected from (C₁-C₄)alkyl, for example methyl; or amino; orwhich is substituted on a ring nitrogen atom with one substituentselected from (C₁-C₄)alkyl, for example methyl; or D, for exampleazetidinyl wherein R³ is hydrogen or (C₁-C₄)alkyl, for example methyl orethyl. Preferably the pyrazolyl is attached to X, or directly to ring Bif X is absent, via a carbon atom, more preferably via a carbon atom atthe 3 position.

In Embodiment (6.8), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein C is pyridinyl, which isunsubstituted, or which is substituted on a ring carbon atom with onesubstituent selected from hydroxy; halo, for example fluoro or chloro;cyano; (C₁-C₄)alkyl, for example methyl; halo(C₁-C₄)alkyl, for exampletrifluoromethyl; (C₁-C₄)alkoxy, for example methoxy; N(R²)₂, wherein R²is selected from hydrogen, or (C₁-C₄)alkyl, for example methyl, or(C₃-C₆)cycloalkyl, for example cyclobutyl, to give for example amino,N(CH₃)₂, NH(cyclobutyl); N(R²)₂(C₁-C₄)alkyl, for exampleN-azetidinylmethyl, 3,3-difluoro-N-azetidinylmethyl;hydroxy(C₁-C₄)alkyl, for example hydroxymethyl; C(O)N(R²)₂, for exampleC(O)N-azetidinyl; (C₃-C₈)cycloalkoxy, for example cyclobutoxy; and D,wherein D is Het¹, for example azetidinyl, morpholinyl, or piperazinyl,all of which are unsubstituted; or D is pyridinyl is substituted on aring nitrogen with hydroxy.

In Embodiment (6.9), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein C is pyridinyl, which issubstituted on a ring carbon atom with one substituent selected fromN(R²)₂, wherein R² is selected from hydrogen, or (C₁-C₄)alkyl, forexample methyl, to give, for example amino, or N(CH₃)₂;N(R²)₂(C₁-C₄)alkyl, wherein R² is selected from hydrogen to give, forexample aminomethyl, or both R² groups are selectived from (C₁-C₄)alkyland are taken together with the N to which they are attached to form a 4memebered ring to give, for example, N-azetidinylmethyl;(C₃-C₈)cycloalkoxy, for example cyclobutoxy; or D where D is Het¹, forexample piperazinyl.

In Embodiment (6.10), invention provides a compound of formula (I), or apharmaceutically acceptable salt, solvate or tautomer thereof, accordingto any preceding Embodiment, wherein C is pyridazinyl, which isunsubstituted; or substituted on a ring carbon with halo, for examplechloro.

In Embodiment (6.11), invention provides a compound of formula (I), or apharmaceutically acceptable salt, solvate or tautomer thereof, accordingto any preceding Embodiment, wherein C is azetidinyl, which ispreferably attached to X via a carbon atom, more preferably the carbonat the 3 position and R³ is selected from H or C(O)(C₁-C₄)alkyl, forexample —C(O)—CH₃, C(O)O(C₁-C₄)alkyl, for example —C(O)O—CH₃.

In Embodiment (6.12), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein C is azetidinyl which isattached to X, or directly to ring B if X is absent, via a carbon atom,more preferably the carbon at the 3 position and where R³ is selectedfrom H.

In Embodiment (6.13), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein C is piperidinyl, whichis preferably attached to X, or directly to ring B if X is absent, via acarbon atom, more preferably the carbon at the 4 position, and whichpiperidinyl is unsubstituted, or which is substituted on a ring carbonwith two substituents selected from halo, for example fluoro; or whereR³ is selected from H, (C₁-C₄)alkyl, for example methyl, orC(O)O(C₁-C₄)alkyl, for example —C(O)O—C(CH₃)₂.

In Embodiment (6.14), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein C is piperidinyl, whichis attached to X, or directly to ring B if X is absent, via a carbonatom at the 4 position and which is unsubstituted.

In Embodiment (6.15), invention provides a compound of formula (I), or apharmaceutically acceptable salt, solvate or tautomer thereof, accordingto any preceding Embodiment, wherein C is tetrahydropyranyl, which ispreferably attached to X, or directly to ring B if X is absent, via acarbon atom, more preferably the carbon at the 4 position, and whichtetrahydropyranyl is unsubstituted.

In Embodiment (6.16), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein C is pyrimidinyl, whichis substituted on a ring carbon atom with one substituent selected fromN(R²)₂, for example amino; or D where D is Het¹, for exampleN-azetidnyl, N-morpholinyl or N-piperazinyl, most preferably piperazinylwherein R₃ is hydrogen.

In Embodiment (7) the invention provides a compound of formula (I), or apharmaceutically acceptable salt, solvate or tautomer thereof, accordingto any preceding Embodiment, wherein X is absent, —O—, methylene, or—O-methylene.

In Embodiment (7.1), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein X is absent.

In Embodiment (7.2), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein when B is phenyl, X isabsent, and C is phenyl; (C₃-C₈)cycloalkyl, for example cyclopropyl;Het¹, for example, azetidinyl, piperidinyl, oxetanyl, tetrahydropyranyl,pyrrolidonyl, imidazolidonyl; phenyl; or Het², for example furanyl,pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,3,4-triazolyl, tetrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, 1-oxa-2,4-diazolyl, pyridinyl, pyrazinyl, pyridazinyl, orpyrimidinyl.

In Embodiment (7.3), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein when B is phenyl, X isabsent, and C is azetidinyl, piperidinyl, tetrahydropyranyl pyrazolyl,pyridinyl, pyridazinyl or pyrimidinyl.

In Embodiment (7.4), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein when B is phenyl, X is O,and C is phenyl; or Het², for example, pyridinyl.

In Embodiment (7.5), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein when B is phenyl, X isCH₂, and C is (C₃-C₈)cycloalkyl, for example cyclopropyl; Het¹, forexample, azetidinyl, morpholinyl, pyrrolidonyl, piperidinyl; or Het²,for example, pyrazolyl, 1,3,4-triazolyl, imidazolyl, isoxazolyl, orpyridinyl.

In Embodiment (7.6), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein when B is phenyl, X isOCH₂, and C phenyl.

In Embodiment (7.7), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein when B is pyrazolyl, X isabsent, and C phenyl; (C₃-C₈)cycloalkyl, for example cyclohexyl; orHet², for example, pyridinyl.

In Embodiment (7.8), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein when B is pyrazolyl, X isCH₂, and C is phenyl.

In Embodiment (7.9), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein when B is thiazolyl, X isCH₂, and C is phenyl.

In Embodiment (7.10), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein when B is pyridinyl, X isabsent, and C is phenyl or Het², for example, pyrazolyl.

In Embodiment (7.11), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein when B is pyridinyl, X isO, and C is phenyl.

In Embodiment (7.12), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein when B is pyrimidnyl, Xis absent, and C is phenyl.

In Embodiment (7.13), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein when B is pyridazinyl, Xis absent, and C is phenyl.

In Embodiment (7.14), the invention provides a compound of formula (I),or a pharmaceutically acceptable salt, solvate or tautomer thereof,according to any preceding Embodiment, wherein when B is pyrazinyl, X isabsent, and C is phenyl.

In Embodiment (8), the invention provides a compound of the formula (Ia)

or a pharmaceutically acceptable salt, solvate or tautomer thereof,wherein Z, Y¹, Y², Y³, Y⁴, X and C are as defined in any of thepreceding Embodiments;each R^(a) is independently selected from the group consisting of halo,cyano, hydroxy, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,halo(C₁-C₄)alkoxy, cyano(C₁-C₄)alkyl, amino, (C₁-C₄)alkylamino,di(C₁-C₄)alkylamino, amino(C₁-C₄)alkyl, (C₁-C₄)alkylamino(C₁-C₄)alkyl,di[(C₁-C₄)alkyl]amino(C₁-C₄)alkyl, trifluoromethylthio,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, —C(O)R², —C(O)OR²,—OC(O)R², —C(O)—N(R²)₂, —CH₂—C(O)R², —CH₂—C(O)OR², —CH₂—OC(O)R²,—CH₂—C(O)—N(R²)₂, S(O)₂R², S(O)₂N(R²)₂, (C₃-C₈)cycloalkyl, and(C₃-C₈)cycloalkyl(C₁-C₄)alkyl;andn is 0, 1 or 2.

It will be appreciated that compounds of the formula (Ia) are alsoembraced by formula (I) and that formula (Ia) is a preferred, sub groupof the formula (I).

In Embodiment (8.1), the invention provides a compound of the formula(Ia) according to Embodiment 8, and C is a 5-membered aromaticheterocyclic group comprising either (a) 1 to 4 nitrogen atoms, (b) oneoxygen or one sulphur atom or (c) 1 oxygen atom or 1 sulphur atom and 1or 2 nitrogen atoms; optionally substituted as defined in Embodiment 1.

In Embodiment (8.2), the invention provides for a compound of formula(Ia) according to Embodiment 8, and each R^(a) is independently selectedfrom the group consisting of halo, cyano, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, amino,(C₁-C₄)alkylamino, di(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkoxy(C₁-C₄)alkyl, —C(O)OR², —C(O)—N(R²)₂, —CH₂—C(O)—N(R²)₂ and(C₃-C₈)cycloalkyl.

In Embodiment (9), the invention provides a compound of the formula (Ib)

or a pharmaceutically acceptable salt, solvate or tautomer thereof,

wherein Z, Y¹, Y², Y³, Y⁴, X and C are as defined in any of thepreceding Embodiments;

each R^(a) is independently selected from the group consisting of halo,cyano, hydroxy, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,halo(C₁-C₄)alkoxy, cyano(C₁-C₄)alkyl, amino, (C₁-C₄)alkylamino,di(C₁-C₄)alkylamino, amino(C₁-C₄)alkyl, (C₁-C₄)alkylamino(C₁-C₄)alkyl,di[(C₁-C₄)alkyl]amino(C₁-C₄)alkyl, trifluoromethylthio,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, —C(O)R², —C(O)OR²,—OC(O)R², —C(O)—N(R²)₂, —CH₂—C(O)R², —CH₂—C(O)OR², —CH₂—OC(O)R²,—CH₂—C(O)—N(R²)₂, S(O)₂R², S(O)₂N(R²)₂, (C₃-C₈)cycloalkyl, and(C₃-C₈)cycloalkyl(C₁-C₄)alkyl;

and

n is 0, 1 or 2.

It will be appreciated that compounds of the formula (Ib) are alsoembraced by formula (I) and that formula (Ib) is a preferred, sub groupof the formula (I).

In Embodiment (9.1), the invention provides a compound of the formula(Ib) according to Embodiment 9, and C is a 5-membered aromaticheterocyclic group comprising either (a) 1 to 4 nitrogen atoms, (b) oneoxygen or one sulphur atom or (c) 1 oxygen atom or 1 sulphur atom and 1or 2 nitrogen atoms; optionally substituted as defined in Embodiment 1.

In Embodiment (9.2), the invention provides a compound of the formula(Ib) according to Embodiment 9, and each R^(a) is independently selectedfrom the group consisting of halo, cyano, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, amino,(C₁-C₄)alkylamino, di(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkoxy(C₁-C₄)alkyl, —C(O)OR², —C(O)—N(R²)₂, —CH₂—C(O)—N(R²)₂ and(C₃-C₈)cycloalkyl.

Specific preferred compounds according to the invention are those listedin the Examples section below and the pharmaceutically acceptable saltsand solvates thereof.

DETAILED DESCRIPTION

As used herein the term compounds of the invention means, unlessotherwise stated, compounds of formula (I), formula (Ia), formula (Ib),and compounds of Embodiment 1, Embodiment 2, Embodiment 2a, Embodiment2.1, Embodiment 2.2, Embodiment 2.2a, Embodiment 2.2b, Embodiment 2.2c,Embodiment 2.3, Embodiment 2.4, Embodiment 2.5, Embodiment 2.5a,Embodiment 2.6, Embodiment 2.7, Embodiment 3, Embodiment 3.1, Embodiment3.2, Embodiment 3.3, Embodiment 4, Embodiment 4.1, Embodiment 4.2,Embodiment 4.3, Embodiment 4.4, Embodiment 4.5, Embodiment 5, Embodiment5a, Embodiment 5b, Embodiment 5c, Embodiment 5.1, Embodiment 5.1a,Embodiment 5.2, Embodiment 5.3, Embodiment 5.4, Embodiment 5.5,Embodiment 5.6, Embodiment 6, Embodiment 6a, Embodiment 6b, Embodiment6c, Embodiment 6d, Embodiment 6.1, Embodiment 6.1a, Embodiment 6.2,Embodiment 6.2a, Embodiment 6.2b, Embodiment 6.3, Embodiment 6.3a,Embodiment 6.4, Embodiment 6.5, Embodiment 6.6, Embodiment 6.6a,Embodiment 6.7, Embodiment 6.8, Embodiment 6.9, Embodiment 6.10,Embodiment 6.11, Embodiment 6.12, Embodiment 6.13, Embodiment 6.14,Embodiment 6.15, Embodiment 6.16, Embodiment 7, Embodiment 7.1,Embodiment 7.2, Embodiment 7.3, Embodiment 7.4, Embodiment 7.5,Embodiment 7.6, Embodiment 7.7, Embodiment 7.8, Embodiment 7.9,Embodiment 7.10, Embodiment 7.11, Embodiment 7.12, Embodiment 7.13,Embodiment 7.14, Embodiment 8, Embodiment 8.1, Embodiment 8.2,Embodiment 9, Embodiment 9.1, and Embodiment 9.2. In each case, wherethe embodiment covers the compound according to the formula below:

it is excluded.

Some compounds of the formula (I), (Ia) or (Ib), according to any one ofthe preceding Embodiments, may exist in several different tautomericforms. Tautomerism, or tautomeric isomerism, occurs where structuralisomers are interconvertible via a low energy barrier. It can take theform of proton tautomerism, so called valence tautomerism in compoundswhich contain an aromatic moiety. In some compounds different tautomericisomers may exist with respect to the position of certain protectinggroups or prodrug moieties. Illustrative examples of such tautomericforms are provided below but one of ordinary skill in the art wouldunderstand that many different tautomeric forms of such compounds may bepossible and that the examples provided below are not exhaustive.Therefore, all references to compound of formula (I), (Ia) or (Ib),according to any one of the preceding Embodiments, should be taken toinclude tautomers thereof, whether illustrated or not. Furthermore, theillustrative examples provided below indicate situations where certainatoms are substituted with hydrogen. However, one of ordinary skill inthe art would also understand that such tautomeric forms may also existwhen such atoms are substituted by certain protecting groups or withprodrug substitutents. As such the disclosure herein is intended to alsodescribe such alternative tautomeric forms. Furthermore, one of ordinaryskill would understand that certain intermediates used in thepreparation of compounds capable of tautomerising are themselves capableof existing in different tautomeric forms.

One such illustrative example is when the compound of formula (I), (Ia)or (Ib), according to any one of the preceding Embodiments, is acompound of the formula (Ic):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

Y¹, Y², Y³, Y⁴, A, B, X and C are as defined in any one of theEmbodiments above;

Y⁵ is NR⁴, oxygen or sulphur atom;

Y⁶ and Y⁷ are each independently selected from CR⁴ or nitrogen atoms;

provided that Y⁵, Y⁶ and Y⁷ cannot all be nitrogen; and

each R⁴ is independently selected from the group consisting of hydrogen,halo, cyano, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,halo(C₁-C₄)alkoxy, (C₃-C₈)cycloalkyl, amino, (C₁-C₄)alkylamino anddi(C₁-C₄)alkylamino;

tautomerism may occur to provide for example, a compound of the formula(Id).

Illustratively, when compounds of formula (Ic) comprise a nitrogen atomat Y⁶ a third tautomer, may also exist which is represented below byformula (Ie) below:

Furthermore, when the compound of formula (I), (Ia) or (Ib), accordingto any one of the preceding Embodiments, is a compound of the formula(If), as shown below, or a pharmaceutically acceptable salt or solvatethereof, wherein:

Y¹, Y², Y³, Y⁴, B, X and C are as defined in any one of the Embodimentsabove;

Y⁸, Y⁹, Y¹⁰ and Y¹¹ are selected from CR⁴, or a nitrogen atom inaccordance with the definition of Z in Embodiment 1 above; and each R⁴is independently selected from the group consisting of hydrogen, halo,cyano, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,(C₃-C₈)cycloalkyl, amino, (C₁-C₄)alkylamino and di(C₁-C₄)alkylamino;tautomerism may occur to provide for example, a compound of the formula(Ig). Additionally, two other tautomers are possible represented byformulae (Ih) possible and if Y⁸ is a nitrogen atom then a compound offormula (II) is possible.

All references to compounds of the invention, or to compounds offormulae (I), (Ia), and (Ib), should therefore be taken to include,where appropriate, the tautomeric isomers of the compounds, asexemplified by formulae (Ic), (Id), (Ie), (If), (Ig), (Ih), and (Ii)above.

Pharmaceutically acceptable salts of the compounds of formula (I)include the acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Examples include the acetate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isothionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate,succinate, tartrate, tosylate and trifluoroacetate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminium, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts.

For a review on suitable salts, see “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

A pharmaceutically acceptable salt of a compound of formula (I) may bereadily prepared by mixing together solutions of the compound of formula(I) and the desired acid or base, as appropriate. The salt mayprecipitate from solution and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionisation in thesalt may vary from completely ionised to almost non-ionised.

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol. Theterm ‘hydrate’ is employed when said solvent is water.

Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionised, partially ionised, or non-ionised. For a review of suchcomplexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August1975).

Hereinafter all references to compounds of formula (I) includereferences to salts, solvates and complexes thereof and to solvates andcomplexes of salts thereof.

The compounds of the invention include compounds of formula (I) ashereinbefore defined, polymorphs, prodrugs (including tautomeric formsof such prodrugs), and isomers thereof (including optical, geometric andtautomeric isomers) as hereinafter defined and isotopically-labeledcompounds of formula (I).

As stated, the invention includes all polymorphs of the compounds offormula (I) as hereinbefore defined.

Also within the scope of the invention are so-called ‘prodrugs’ of thecompounds of formula (I). Thus certain derivatives of compounds offormula (I) which may have little or no pharmacological activitythemselves can, when administered into or onto the body, be convertedinto compounds of formula (I) having the desired activity, for example,by hydrolytic cleavage. Such derivatives are referred to as ‘prodrugs’.Further information on the use of prodrugs may be found in ‘Pro-drugs asNovel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and WStella) and ‘Bioreversible Carriers in Drug Design’, Pergamon Press,1987 (ed. E B Roche, American Pharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds offormula (I) with certain moieties known to those skilled in the art as‘pro-moieties’as described, for example, in “Design of Prodrugs” by HBundgaard (Elsevier, 1985).

One skilled in the art would recognise that many different pro-drugforms of compounds of the present invention are possible. However, someillustrative examples of prodrugs in accordance with the inventioninclude:

(i) where the compound of formula (I) contains a carboxylic acidfunctionality

(—COOH), an ester thereof, for example, replacement of the hydrogen with(C₁-C₈)alkyl;

(ii) where the compound of formula (I) contains an alcohol functionality(—OH), an ether thereof, for example, replacement of the hydrogen with(C₁-C₆)alkanoyloxymethyl; and

(iii) where the compound of formula (I) contains a primary or secondaryamino functionality (—NH₂ or —NHR where R≠H), an amide thereof, forexample, replacement of one or both hydrogens with (C₁-C₁₀)alkanoyl.

A particularly useful prodrug of compounds of formula (I) which have ageneral formula (Ic), is formed by replacement of the hydrogen of the—NH-group of the sulphonamide moiety or the hydrogen of the —NH-group ofthe 1,3-thiazolyl ring of such compounds is replaced by a prodrug moiety(Prodrug) which is either —CH₂OP(═O)(OR′)₂ or —CH₂C(═O)R′ wherein R′ isselected from the group consisting of hydrogen or (C₁-C₆)alkyl, forexample —C(CH₃)₃. Such compounds are prepared by reaction of the—NH-group of the sulphonamide moiety or the —NH-group of the1,3-thiazolyl ring of the compounds of formula (Ic) with either an alkyllinked phosphate, such as an alkyl linked phosphoric acid or an alkyllinked phosphate ester, or with an alkyl linked carboxylic acid group,such as an alkyl linked carboxylic acid or an alkyl linked carboxylicester. Such prodrug compounds can generally be schematically representedas shown below by formula (Ic′) or its tautomeric form (Id′):

wherein C, X, B, Y¹, Y², Y³, Y⁴, Y⁵, Y⁶, Y⁷ are as defined above forcompounds of formula (Ic) and Prodrug is a prodrug moiety as definedabove. Phosphate prodrugs have been generally described in, for example,Rautio, J.; Kumpulainen, H.; Heimbach, T.; Oliyai, R.; Oh, D.; Järvinen,T.; Savolainen, J. Nat. Rev. Drug Discovery 2008, 7, 255. Carboxylicacid and related ester prodrugs have been generally described inCalheiros, T.; Iley, J.; Lopes, F.; Moreira, R. Bioorg. Med. Chem. Lett.1995, 5, 937 and in Lopes, F.; Moreira, R.; Iley, J. Bioorg. Med. Chem.2000, 8, 707.

When forming such prodrugs it is preferred that the hydrogen of the—NH-group of the sulphonamide moiety or the hydrogen of the —NH-group ofthe 1,3-thiazolyl ring of such compounds is replaced by—CH₂OP(═O)(OR′)₂, in particular wherein R′ is hydrogen to give—CH₂OP(═O)(OH)₂, or where R′ is —C(CH₃)₃ to give —CH₂OP(═O)(OC(CH₃)₃)₂.

As such, in yet another embodiment, Embodiment 10, the inventionprovides for a prodrug of compounds of formula (Ic′) wherein thehydrogen of the —NH-group of the sulphonamide moiety or the hydrogen ofthe —NH-group of the 1,3-thiazolyl ring of such compounds is replaced byeither —CH₂OP(═O)(OR′)₂ or —CH₂C(═O)R′ wherein R′ is selected from thegroup consisting of hydrogen or (C₁-C₆)alkyl, for example —C(CH₃)₃, or apharmaceutically acceptable salt, solvate or tautomer thereof.

Further examples of replacement groups in accordance with the foregoingexamples and examples of other prodrug types may be found in theaforementioned references.

As used herein, unless otherwise specified, references to formula (I)also encompass references to prodrugs, and salts, solvates or tautomersthereof, such as those of Embodiment (10).

Finally, certain compounds of formula (I) may themselves act as prodrugsof other compounds of formula (I).

Compounds of formula (I) containing one or more asymmetric carbon atomscan exist as two or more stereoisomers. Where a compound of formula (I)contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E)isomers are possible. Where the compound contains, for example, a ketoor oxime group or an aromatic moiety, tautomeric isomerism(‘tautomerism’) can occur. It follows that a single compound may exhibitmore than one type of isomerism.

Included within the scope of the present invention are allstereoisomers, geometric isomers and tautomeric forms of the compoundsof formula (I), including compounds exhibiting more than one type ofisomerism, and mixtures of one or more thereof. Also included are acidaddition or base salts wherein the counterion is optically active, forexample, D-lactate or L-lysine, or racemic, for example, DL-tartrate orDL-arginine.

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallisation.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC)

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound of formula (I) contains an acidic or basicmoiety, an acid or base such as tartaric acid or 1-phenylethylamine. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, typically heptane or hexane, containing from 0 to 50%isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine,typically 0.1% diethylamine. Concentration of the eluate affords theenriched mixture.

Stereoisomeric conglomerates may be separated by conventional techniquesknown to those skilled in the art—see, for example, “Stereochemistry ofOrganic Compounds” by E L Eliel (Wiley, New York, 1994).

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of formula (I) wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number usuallyfound in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include isotopes of hydrogen, such as ²H and ³H, carbon, suchas ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S.

Certain isotopically-labelled compounds of formula (I), for example,those incorporating a radioactive isotope, are useful in drug and/orsubstrate tissue distribution studies. The radioactive isotopes tritium,i.e. ³H, and carbon-14, i.e. ¹⁴C, and ¹²⁵I are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagents in placeof the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

The compounds of formula (I), being Nav1.7 channel modulators, arepotentially useful in the treatment of a range of disorders. Thetreatment of pain, particularly neuropathic, nociceptive andinflammatory pain, is a preferred use.

Physiological pain is an important protective mechanism designed to warnof danger from potentially injurious stimuli from the externalenvironment. The system operates through a specific set of primarysensory neurones and is activated by noxious stimuli via peripheraltransducing mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164for a review). These sensory fibres are known as nociceptors and arecharacteristically small diameter axons with slow conduction velocities.Nociceptors encode the intensity, duration and quality of noxiousstimulus and by virtue of their topographically organised projection tothe spinal cord, the location of the stimulus. The nociceptors are foundon nociceptive nerve fibres of which there are two main types, A-deltafibres (myelinated) and C fibres (non-myelinated). The activitygenerated by nociceptor input is transferred, after complex processingin the dorsal horn, either directly, or via brain stem relay nuclei, tothe ventrobasal thalamus and then on to the cortex, where the sensationof pain is generated.

Pain may generally be classified as acute or chronic. Acute pain beginssuddenly and is short-lived (usually twelve weeks or less). It isusually associated with a specific cause such as a specific injury andis often sharp and severe. It is the kind of pain that can occur afterspecific injuries resulting from surgery, dental work, a strain or asprain. Acute pain does not generally result in any persistentpsychological response. In contrast, chronic pain is long-term pain,typically persisting for more than three months and leading tosignificant psychological and emotional problems. Common examples ofchronic pain are neuropathic pain (e.g. painful diabetic neuropathy,postherpetic neuralgia), carpal tunnel syndrome, back pain, headache,cancer pain, arthritic pain and chronic post-surgical pain.

When a substantial injury occurs to body tissue, via disease or trauma,the characteristics of nociceptor activation are altered and there issensitisation in the periphery, locally around the injury and centrallywhere the nociceptors terminate. These effects lead to a hightenedsensation of pain. In acute pain these mechanisms can be useful, inpromoting protective behaviours which may better enable repair processesto take place. The normal expectation would be that sensitivity returnsto normal once the injury has healed. However, in many chronic painstates, the hypersensitivity far outlasts the healing process and isoften due to nervous system injury. This injury often leads toabnormalities in sensory nerve fibres associated with maladaptation andaberrant activity (Woolf & Salter, 2000, Science, 288, 1765-1768).

Clinical pain is present when discomfort and abnormal sensitivityfeature among the patient's symptoms. Patients tend to be quiteheterogeneous and may present with various pain symptoms. Such symptomsinclude: 1) spontaneous pain which may be dull, burning, or stabbing; 2)exaggerated pain responses to noxious stimuli (hyperalgesia); and 3)pain produced by normally innocuous stimuli (allodynia—Meyer et al.,1994, Textbook of Pain, 13-44). Although patients suffering from variousforms of acute and chronic pain may have similar symptoms, theunderlying mechanisms may be different and may, therefore, requiredifferent treatment strategies. Pain can also therefore be divided intoa number of different subtypes according to differing pathophysiology,including nociceptive, inflammatory and neuropathic pain.

Nociceptive pain is induced by tissue injury or by intense stimuli withthe potential to cause injury. Pain afferents are activated bytransduction of stimuli by nociceptors at the site of injury andactivate neurons in the spinal cord at the level of their termination.This is then relayed up the spinal tracts to the brain where pain isperceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activationof nociceptors activates two types of afferent nerve fibres. MyelinatedA-delta fibres transmit rapidly and are responsible for sharp andstabbing pain sensations, whilst unmyelinated C fibres transmit at aslower rate and convey a dull or aching pain. Moderate to severe acutenociceptive pain is a prominent feature of pain from central nervoussystem trauma, strains/sprains, burns, myocardial infarction and acutepancreatitis, post-operative pain (pain following any type of surgicalprocedure), posttraumatic pain, renal colic, cancer pain and back pain.Cancer pain may be chronic pain such as tumour related pain (e.g. bonepain, headache, facial pain or visceral pain) or pain associated withcancer therapy (e.g. postchemotherapy syndrome, chronic postsurgicalpain syndrome or post radiation syndrome). Cancer pain may also occur inresponse to chemotherapy, immunotherapy, hormonal therapy orradiotherapy. Back pain may be due to herniated or rupturedintervertabral discs or abnormalities of the lumber facet joints,sacroiliac joints, paraspinal muscles or the posterior longitudinalligament. Back pain may resolve naturally but in some patients, where itlasts over 12 weeks, it becomes a chronic condition which can beparticularly debilitating.

Neuropathic pain is currently defined as pain initiated or caused by aprimary lesion or dysfunction in the nervous system. Nerve damage can becaused by trauma and disease and thus the term ‘neuropathic pain’encompasses many disorders with diverse aetiologies. These include, butare not limited to, peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy,HIV neuropathy, phantom limb pain, carpal tunnel syndrome, centralpost-stroke pain and pain associated with chronic alcoholism,hypothyroidism, uremia, multiple sclerosis, spinal cord injury,Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic painis pathological as it has no protective role. It is often present wellafter the original cause has dissipated, commonly lasting for years,significantly decreasing a patient's quality of life (Woolf and Mannion,1999, Lancet, 353, 1959-1964). The symptoms of neuropathic pain aredifficult to treat, as they are often heterogeneous even betweenpatients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6,S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). Theyinclude spontaneous pain, which can be continuous, and paroxysmal orabnormal evoked pain, such as hyperalgesia (increased sensitivity to anoxious stimulus) and allodynia (sensitivity to a normally innocuousstimulus).

The inflammatory process is a complex series of biochemical and cellularevents, activated in response to tissue injury or the presence offoreign substances, which results in swelling and pain (Levine andTaiwo, 1994, Textbook of Pain, 45-56). Arthritic pain is the most commoninflammatory pain. Rheumatoid disease is one of the commonest chronicinflammatory conditions in developed countries and rheumatoid arthritisis a common cause of disability. The exact aetiology of rheumatoidarthritis is unknown, but current hypotheses suggest that both geneticand microbiological factors may be important (Grennan & Jayson, 1994,Textbook of Pain, 397-407). It has been estimated that almost 16 millionAmericans have symptomatic osteoarthritis (OA) or degenerative jointdisease, most of whom are over 60 years of age, and this is expected toincrease to 40 million as the age of the population increases, makingthis a public health problem of enormous magnitude (Houge & Mersfelder,2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook ofPain, 387-395). Most patients with osteoarthritis seek medical attentionbecause of the associated pain. Arthritis has a significant impact onpsychosocial and physical function and is known to be the leading causeof disability in later life. Ankylosing spondylitis is also a rheumaticdisease that causes arthritis of the spine and sacroiliac joints. Itvaries from intermittent episodes of back pain that occur throughoutlife to a severe chronic disease that attacks the spine, peripheraljoints and other body organs.

Another type of inflammatory pain is visceral pain which includes painassociated with inflammatory bowel disease (IBD). Visceral pain is painassociated with the viscera, which encompass the organs of the abdominalcavity. These organs include the sex organs, spleen and part of thedigestive system. Pain associated with the viscera can be divided intodigestive visceral pain and non-digestive visceral pain. Commonlyencountered gastrointestinal (GI) disorders that cause pain includefunctional bowel disorder (FBD) and inflammatory bowel disease (IBD).These GI disorders include a wide range of disease states that arecurrently only moderately controlled, including, in respect of FBD,gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) andfunctional abdominal pain syndrome (FAPS), and, in respect of IBD,Crohn's disease, ileitis and ulcerative colitis, all of which regularlyproduce visceral pain. Other types of visceral pain include the painassociated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.

It should be noted that some types of pain have multiple aetiologies andthus can be classified in more than one area, e.g. back pain and cancerpain have both nociceptive and neuropathic components.

Other types of pain include:

-   -   pain resulting from musculo-skeletal disorders, including        myalgia, fibromyalgia, spondylitis, sero-negative        (non-rheumatoid) arthropathies, non-articular rheumatism,        dystrophinopathy, glycogenolysis, polymyositis and pyomyositis;    -   heart and vascular pain, including pain caused by angina,        myocardical infarction, mitral stenosis, pericarditis, Raynaud's        phenomenon, scleredoma and skeletal muscle ischemia;    -   head pain, such as migraine (including migraine with aura and        migraine without aura), cluster headache, tension-type headache        mixed headache and headache associated with vascular disorders;    -   erythermalgia; and    -   orofacial pain, including dental pain, otic pain, burning mouth        syndrome and temporomandibular myofascial pain.

Compounds of the invention intended for pharmaceutical use may beadministered as crystalline or amorphous products. They may be obtained,for example, as solid plugs, powders, or films by methods such asprecipitation, crystallization, freeze drying, spray drying, orevaporative drying. Microwave or radio frequency drying may be used forthis purpose.

They may be administered alone or in combination with one or more othercompounds of the invention or in combination with one or more otherdrugs (or as any combination thereof). Generally, they will beadministered as a formulation in association with one or morepharmaceutically acceptable excipients. The term “excipient” is usedherein to describe any ingredient other than the compound(s) of theinvention. The choice of excipient will to a large extent depend onfactors such as the particular mode of administration, the effect of theexcipient on solubility and stability, and the nature of the dosageform.

Pharmaceutical compositions suitable for the delivery of compounds ofthe present invention and methods for their preparation will be readilyapparent to those skilled in the art. Such compositions and methods fortheir preparation may be found, for example, in ‘Remington'sPharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995).

Oral Administration

The compounds of the invention may be administered orally. Oraladministration may involve swallowing, so that the compound enters thegastrointestinal tract, or buccal or sublingual administration may beemployed by which the compound enters the blood stream directly from themouth.

Formulations suitable for oral administration include solid formulationssuch as tablets, capsules containing particulates, liquids, or powders,lozenges (including liquid-filled), chews, multi- and nano-particulates,gels, solid solution, liposome, films (including muco-adhesive), ovules,sprays and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations may be employed as fillers in soft or hard capsulesand typically comprise a carrier, for example, water, ethanol,polyethylene glycol, propylene glycol, methylcellulose, or a suitableoil, and one or more emulsifying agents and/or suspending agents. Liquidformulations may also be prepared by the reconstitution of a solid, forexample, from a sachet.

The compounds of the invention may also be used in fast-dissolving,fast-disintegrating dosage forms such as those described in ExpertOpinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen(2001).

For tablet dosage forms, depending on dose, the drug may make up from 1wt % to 80 wt % of the dosage form, more typically from 5 wt % to 60 wt% of the dosage form. In addition to the drug, tablets generally containa disintegrant. Examples of disintegrants include sodium starchglycolate, sodium carboxymethyl cellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone,methyl cellulose, microcrystalline cellulose, lower alkyl-substitutedhydroxypropyl cellulose, starch, pregelatinised starch and sodiumalginate. Generally, the disintegrant will comprise from 1 wt % to 25 wt%, preferably from 5 wt % to 20 wt % of the dosage form.

Binders are generally used to impart cohesive qualities to a tabletformulation. Suitable binders include microcrystalline cellulose,gelatin, sugars, polyethylene glycol, natural and synthetic gums,polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose andhydroxypropyl methylcellulose. Tablets may also contain diluents, suchas lactose (monohydrate, spray-dried monohydrate, anhydrous and thelike), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystallinecellulose, starch and dibasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such assodium lauryl sulfate and polysorbate 80, and glidants such as silicondioxide and talc. When present, surface active agents may comprise from0.2 wt % to 5 wt % of the tablet, and glidants may comprise from 0.2 wt% to 1 wt % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate,calcium stearate, zinc stearate, sodium stearyl fumarate, and mixturesof magnesium stearate with sodium lauryl sulphate. Lubricants generallycomprise from 0.25 wt % to 10 wt %, preferably from 0.5 wt % to 3 wt %of the tablet.

Other possible ingredients include anti-oxidants, colourants, flavouringagents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 wt % toabout 90 wt % binder, from about 0 wt % to about 85 wt % diluent, fromabout 2 wt % to about 10 wt % disintegrant, and from about 0.25 wt % toabout 10 wt % lubricant.

Tablet blends may be compressed directly or by roller to form tablets.Tablet blends or portions of blends may alternatively be wet-, dry-, ormelt-granulated, melt congealed, or extruded before tabletting. Thefinal formulation may comprise one or more layers and may be coated oruncoated; it may even be encapsulated.

The formulation of tablets is discussed in “Pharmaceutical Dosage Forms:Tablets, Vol. 1”, by H. Lieberman and L. Lachman, Marcel Dekker, N.Y.,N.Y., 1980 (ISBN 0-8247-6918-X).

Solid formulations for oral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Suitable modified release formulations for the purposes of the inventionare described in U.S. Pat. No. 6,106,864. Details of other suitablerelease technologies such as high energy dispersions and osmotic andcoated particles are to be found in Verma et al, PharmaceuticalTechnology On-line, 25(2), 1-14 (2001). The use of chewing gum toachieve controlled release is described in WO 00/35298.

Parenteral Administration

The compounds of the invention may also be administered directly intothe blood stream, into muscle, or into an internal organ. Suitable meansfor parenteral administration include intravenous, intraarterial,intraperitoneal, intrathecal, intraventricular, intraurethral,intrasternal, intracranial, intramuscular and subcutaneous. Suitabledevices for parenteral administration include needle (includingmicroneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which maycontain excipients such as salts, carbohydrates and buffering agents(preferably to a pH of from 3 to 9), but, for some applications, theymay be more suitably formulated as a sterile non-aqueous solution or asa dried form to be used in conjunction with a suitable vehicle such assterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, forexample, by lyophilisation, may readily be accomplished using standardpharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula (I) used in the preparation ofparenteral solutions may be increased by the use of appropriateformulation techniques, such as the incorporation ofsolubility-enhancing agents.

Formulations for parenteral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease. Thus compounds of the invention may be formulated as a solid,semi-solid, or thixotropic liquid for administration as an implanteddepot providing modified release of the active compound. Examples ofsuch formulations include drug-coated stents and PGLA microspheres.

Topical Administration

The compounds of the invention may also be administered topically to theskin or mucosa, that is, dermally or transdermally. Typical formulationsfor this purpose include gels, hydrogels, lotions, solutions, creams,ointments, dusting powders, dressings, foams, films, skin patches,wafers, implants, sponges, fibres, bandages and microemulsions.Liposomes may also be used. Typical carriers include alcohol, water,mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethyleneglycol and propylene glycol. Penetration enhancers may beincorporated—see, for example, J Pharm Sci, 88 (10), 955-958 by Finninand Morgan (October 1999).

Other means of topical administration include delivery byelectroporation, iontophoresis, phonophoresis, sonophoresis andmicroneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

Formulations for topical administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Inhaled/Intranasal Administration

The compounds of the invention can also be administered intranasally orby inhalation, typically in the form of a dry powder (either alone, as amixture, for example, in a dry blend with lactose, or as a mixedcomponent particle, for example, mixed with phospholipids, such asphosphatidylcholine) from a dry powder inhaler or as an aerosol sprayfrom a pressurised container, pump, spray, atomiser (preferably anatomiser using electrohydrodynamics to produce a fine mist), ornebuliser, with or without the use of a suitable propellant, such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Forintranasal use, the powder may comprise a bioadhesive agent, forexample, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser containsa solution or suspension of the compound(s) of the invention comprising,for example, ethanol, aqueous ethanol, or a suitable alternative agentfor dispersing, solubilising, or extending release of the active, apropellant(s) as solvent and an optional surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug productis micronised to a size suitable for delivery by inhalation (typicallyless than 5 microns). This may be achieved by any appropriatecomminuting method, such as spiral jet milling, fluid bed jet milling,supercritical fluid processing to form nanoparticles, high pressurehomogenisation, or spray drying.

Capsules (made, for example, from gelatin or HPMC), blisters andcartridges for use in an inhaler or insufflator may be formulated tocontain a powder mix of the compound of the invention, a suitable powderbase such as lactose or starch and a performance modifier such asl-leucine, mannitol, or magnesium stearate. The lactose may be anhydrousor in the form of the monohydrate, preferably the latter. Other suitableexcipients include dextran, glucose, maltose, sorbitol, xylitol,fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomiser usingelectrohydrodynamics to produce a fine mist may contain from 1 μg to 20mg of the compound of the invention per actuation and the actuationvolume may vary from 1 μl to 100 μl. A typical formulation may comprisea compound of formula (I), propylene glycol, sterile water, ethanol andsodium chloride. Alternative solvents which may be used instead ofpropylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or sweeteners, suchas saccharin or saccharin sodium, may be added to those formulations ofthe invention intended for inhaled/intranasal administration.

Formulations for inhaled/intranasal administration may be formulated tobe immediate and/or modified release using, for example,poly(DL-lactic-coglycolic acid (PGLA). Modified release formulationsinclude delayed-, sustained-, pulsed-, controlled-, targeted andprogrammed release.

In the case of dry powder inhalers and aerosols, the dosage unit isdetermined by means of a valve which delivers a metered amount. Units inaccordance with the invention are typically arranged to administer ametered dose or “puff” containing the compound of formula (I). Theoverall daily dose may be administered in a single dose or, moreusually, as divided doses throughout the day.

Rectal/Intravaginal Administration

The compounds of the invention may be administered rectally orvaginally, for example, in the form of a suppository, pessary, or enema.Cocoa butter is a traditional suppository base, but various alternativesmay be used as appropriate.

Formulations for rectal/vaginal administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted and programmedrelease.

Ocular/Aural Administration

The compounds of the invention may also be administered directly to theeye or ear, typically in the form of drops of a micronised suspension orsolution in isotonic, pH-adjusted, sterile saline. Other formulationssuitable for ocular and aural administration include ointments,biodegradable (e.g. absorbable gel sponges, collagen) andnon-biodegradable (e.g. silicone) implants, wafers, lenses andparticulate or vesicular systems, such as niosomes or liposomes. Apolymer such as crossed-linked polyacrylic acid, polyvinylalcohol,hyaluronic acid, a cellulosic polymer, for example,hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or a heteropolysaccharide polymer, for example, gelan gum,may be incorporated together with a preservative, such as benzalkoniumchloride. Such formulations may also be delivered by iontophoresis.

Formulations for ocular/aural administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted, or programmedrelease.

Other Technologies

The compounds of the invention may be combined with solublemacromolecular entities, such as cyclodextrin and suitable derivativesthereof or polyethylene glycol-containing polymers, in order to improvetheir solubility, dissolution rate, taste-masking, bioavailabilityand/or stability for use in any of the aforementioned modes ofadministration.

Drug-cyclodextrin complexes, for example, are found to be generallyuseful for most dosage forms and administration routes. Both inclusionand non-inclusion complexes may be used. As an alternative to directcomplexation with the drug, the cyclodextrin may be used as an auxiliaryadditive, i.e. as a carrier, diluent, or solubiliser. Most commonly usedfor these purposes are alpha-, beta- and gamma-cyclodextrins, examplesof which may be found in International Patent Applications Nos. WO91/11172, WO 94/02518 and WO 98/55148.

Kit-of-Parts

Inasmuch as it may desirable to administer a combination of activecompounds, for example, for the purpose of treating a particular diseaseor condition, it is within the scope of the present invention that twoor more pharmaceutical compositions, at least one of which contains acompound in accordance with the invention, may conveniently be combinedin the form of a kit suitable for coadministration of the compositions.

Thus the kit of the invention comprises two or more separatepharmaceutical compositions, at least one of which contains a compoundof formula (I) in accordance with the invention, and means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is the familiarblister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administeringdifferent dosage forms, for example, oral and parenteral, foradministering the separate compositions at different dosage intervals,or for titrating the separate compositions against one another. Toassist compliance, the kit typically comprises directions foradministration and may be provided with a so-called memory aid.

Dosage

For administration to human patients, the total daily dose of thecompounds of the invention depends, of course, on the mode ofadministration. For example, oral administration may require a highertotal daily dose, than an intravenous dose. The total daily dose may beadministered in single or divided doses.

For the avoidance of doubt, references herein to “treatment” includereferences to curative, palliative and prophylactic treatment.

Combinations

A Nav1.7 channel modulator may be usefully combined with anotherpharmacologically active compound, or with two or more otherpharmacologically active compounds, particularly in the treatment ofpain. For example, a Nav1.7 channel modulator, particularly a compoundof formula (I), or a pharmaceutically acceptable salt, solvate ortautomer thereof, as defined above, may be administered simultaneously,sequentially or separately in combination with one or more agentsselected from:

-   -   an alternative Nav1.7 channel modulator, for example one or more        alternative compounds of the present invention, or alternatively        those compounds disclosed in WO 2009/012242;    -   an alternative sodium channel modulator, such as a Nav1.3        modulator, for example those disclosed in WO 2008/118758; or a        Nav1.8 modulator, for example those disclosed in WO 2008/135826,        more particularly        N-[6-Amino-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl]-1-methyl-1H-pyrazole-5-carboxamide;    -   a compound which increases the levels of endocannabinoid such as        compounds with fatty acid amid hydrolase inhibitory (FAAH)        activity, in particular those disclosed in WO 2008/047229, more        particularly        N-pyridazin-3-yl-4-(3-{[5-(trifluoromethyl)pyridine-2-yl]oxy}benzylidene)piperidine-1-carboxamide;    -   a compound which is an inhibitor of mPGEs-1;    -   an opioid analgesic, e.g. morphine, heroin, hydromorphone,        oxymorphone, levorphanol, levallorphan, methadone, meperidine,        fentanyl, cocaine, codeine, dihydrocodeine, oxycodone,        hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone,        naltrexone, buprenorphine, butorphanol, nalbuphine or        pentazocine;    -   a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin,        diclofenac, diflusinal, etodolac, fenbufen, fenoprofen,        flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen,        ketorolac, meclofenamic acid, mefenamic acid, meloxicam,        nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine,        oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac,        tolmetin or zomepirac;    -   a barbiturate sedative, e.g. amobarbital, aprobarbital,        butabarbital, butabital, mephobarbital, metharbital,        methohexital, pentobarbital, phenobartital, secobarbital,        talbutal, theamylal or thiopental;    -   a benzodiazepine having a sedative action, e.g.        chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam,        oxazepam, temazepam or triazolam;    -   an H₁ antagonist having a sedative action, e.g. diphenhydramine,        pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;    -   a sedative such as glutethimide, meprobamate, methaqualone or        dichloralphenazone;    -   a skeletal muscle relaxant, e.g. baclofen, carisoprodol,        chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;    -   an NMDA receptor antagonist, e.g. dextromethorphan        ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan        ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine,        pyrroloquinoline quinine,        cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine,        EN-3231 (MorphiDex®, a combination formulation of morphine and        dextromethorphan), topiramate, neramexane or perzinfotel        including an NR2B antagonist, e.g. ifenprodil, traxoprodil or        (−)—(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;    -   an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine,        guanfacine, dexmetatomidine, modafinil, or        4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)        quinazoline;    -   a tricyclic antidepressant, e.g. desipramine, imipramine,        amitriptyline or nortriptyline;    -   an anticonvulsant, e.g. carbamazepine, lamotrigine, topiratmate        or valproate;    -   a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1        antagonist, e.g.        (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione        (TAK-637),        5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one        (MK-869), aprepitant, lanepitant, dapitant or        3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine        (2S,3S);    -   a muscarinic antagonist, e.g oxybutynin, tolterodine,        propiverine, tropsium chloride, darifenacin, solifenacin,        temiverine and ipratropium;    -   a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib,        parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;    -   a coal-tar analgesic, in particular paracetamol;    -   a neuroleptic such as droperidol, chlorpromazine, haloperidol,        perphenazine, thioridazine, mesoridazine, trifluoperazine,        fluphenazine, clozapine, olanzapine, risperidone, ziprasidone,        quetiapine, sertindole, aripiprazole, sonepiprazole,        blonanserin, iloperidone, perospirone, raclopride, zotepine,        bifeprunox, asenapine, lurasidone, amisulpride, balaperidone,        palindore, eplivanserin, osanetant, rimonabant, meclinertant,        Miraxion® or sarizotan;    -   a vanilloid receptor agonist (e.g. resinferatoxin) or antagonist        (e.g. capsazepine);    -   a beta-adrenergic such as propranolol;    -   a local anaesthetic such as mexiletine;    -   a corticosteroid such as dexamethasone;    -   a 5-HT receptor agonist or antagonist, particularly a        5-HT_(1B/1D) agonist such as eletriptan, sumatriptan,        naratriptan, zolmitriptan or rizatriptan;    -   a 5-HT_(2A) receptor antagonist such as        R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol        (MDL-100907);    -   a cholinergic (nicotinic) analgesic, such as ispronicline        (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine        (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine        (ABT-594) or nicotine;    -   Tramadol®;    -   a PDEV inhibitor, such as        5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one        (sildenafil),        (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]-pyrido[3,4-b]indole-1,4-dione        (IC-351 or tadalafil),        2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one        (vardenafil),        5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,        5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,        5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,        4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide,        3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;    -   an alpha-2-delta ligand such as gabapentin, pregabalin,        3-methylgabapentin,        (1α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,        (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid,        (3S,5R)-3-amino-5-methyl-heptanoic acid,        (3S,5R)-3-amino-5-methyl-octanoic acid,        (2S,4S)-4-(3-chlorophenoxy)proline,        (2S,4S)-4-(3-fluorobenzyl)-proline,        [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,        3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,        C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,        (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid,        (3S,5R)-3-aminomethyl-5-methyl-octanoic acid,        (3S,5R)-3-amino-5-methyl-nonanoic acid,        (3S,5R)-3-amino-5-methyl-octanoic acid,        (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and        (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;    -   a cannabinoid;    -   metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;    -   a serotonin reuptake inhibitor such as sertraline, sertraline        metabolite demethylsertraline, fluoxetine, norfluoxetine        (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine,        citalopram, citalopram metabolite desmethylcitalopram,        escitalopram, d,l-fenfluramine, femoxetine, ifoxetine,        cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine        and trazodone;    -   a noradrenaline (norepinephrine) reuptake inhibitor, such as        maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,        tomoxetine, mianserin, buproprion, buproprion metabolite        hydroxybuproprion, nomifensine and viloxazine (Vivalan®),        especially a selective noradrenaline reuptake inhibitor such as        reboxetine, in particular (S,S)-reboxetine;    -   a dual serotonin-noradrenaline reuptake inhibitor, such as        venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,        clomipramine, clomipramine metabolite desmethylclomipramine,        duloxetine, milnacipran and imipramine;    -   an inducible nitric oxide synthase (iNOS) inhibitor such as        S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine,        S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine,        S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine,        (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic        acid,        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarbonitrile;        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile,        (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol,        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)        butyl]thio]-6-(trifluoromethyl)-3 pyridinecarbonitrile,        2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile,        N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine,        or guanidinoethyldisulfide;    -   an acetylcholinesterase inhibitor such as donepezil;    -   a prostaglandin E₂ subtype 4 (EP4) antagonist such as        N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide        or        4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic        acid;    -   a leukotriene B4 antagonist; such as        1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic        acid (CP-105696),        5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric        acid (ONO-4057) or DPC-11870,    -   a 5-lipoxygenase inhibitor, such as zileuton,        6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone        (ZD-2138), or        2,3,5-trimethyl-6-(3-pyridylmethyl),1,4-benzoquinone (CV-6504);    -   a sodium channel blocker, such as lidocaine;    -   a 5-HT3 antagonist, such as ondansetron;        and the pharmaceutically acceptable salts and solvates thereof.

Such combinations offer significant advantages, including synergisticactivity, in therapy.

Inasmuch as it may desirable to administer a combination of activecompounds, for example, for the purpose of treating a particular diseaseor condition, it is within the scope of the present invention that twoor more pharmaceutical compositions, at least one of which contains acompound in accordance with the invention, may conveniently be combinedin the form of a kit suitable for coadministration of the compositions.

Thus the kit of the invention comprises two or more separatepharmaceutical compositions, at least one of which contains a compoundof formula (I) in accordance with the invention, and means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is the familiarblister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administeringdifferent dosage forms, for example, oral and parenteral, foradministering the separate compositions at different dosage intervals,or for titrating the separate compositions against one another. Toassist compliance, the kit typically comprises directions foradministration and may be provided with a so-called memory aid.

It will be appreciated that the invention exists in a number ofdifferent embodiments including:

-   (i) a compound of formula (I) or a pharmaceutically acceptable salt,    solvate or tautomer thereof;-   (ii) a process for the preparation of a compound of formula (I) or a    pharmaceutically acceptable salt, solvate or tautomer thereof;-   (iii) a pharmaceutical composition including a compound of    formula (I) or a pharmaceutically acceptable salt, solvate or    tautomer thereof, together with a pharmaceutically acceptable    excipient;-   (iv) a pharmaceutical composition including a compound of    formula (I) or a pharmaceutically acceptable salt, solvate or    tautomer thereof, together with a pharmaceutically acceptable    excipient, for use in the treatment of a disease or condition for    which a Nav1.7 channel modulator is indicated, particularly for the    treatment of pain;-   (v) a compound of formula (I) or a pharmaceutically acceptable salt,    solvate or composition thereof, for use as a medicament;-   (vi) the use of a compound of formula (I) or of a pharmaceutically    acceptable salt, solvate or composition thereof, for the manufacture    of a medicament to treat a disease or condition for which a Nav1.7    channel modulator is indicated, particularly for the treatment of    pain;-   (vii) a compound of formula (I) or of a pharmaceutically acceptable    salt, solvate or composition thereof, for use in the treatment of a    disease or condition for which a Nav1.7 channel modulator is    indicated, particularly for use in the treatment of pain;-   (viii) a method of treating a disease or condition for which a    Nav1.7 channel modulator is indicated in a mammal, including a human    being, including administering to said mammal an effective amount of    a compound of formula (I) or a pharmaceutically acceptable salt,    solvate or composition thereof.

All of the compounds of the formula (I) can be prepared by theprocedures described in the general methods presented below or by thespecific methods described in the Examples section and the Preparationssection, or by routine modifications thereof which can be made byemploying the common general knowledge of one skilled in the art (see,for example, Comprehensive Organic Chemistry, Ed Barton and Ollis,Elsevier; Comprehensive Organic Transformations: A guide to FunctionalGroup preparations, Larock, John Wiley & Sons). The present inventionalso encompasses any one or more of these processes for preparing thecompounds of formula (I), in addition to any novel intermediates usedtherein.

In the following general methods, Z, Y¹, Y², Y³, Y⁴, B, X, C and D areas previously defined for a compound of the formula (I) unless otherwisestated.

Compounds of the present invention can be prepared using readilyavailable starting materials or known intermediates. The syntheticschemes set forth below provide exemplary synthetic pathways for thepreparation of compounds of the invention.

When preparing derivatives of formula (I) in accordance with theinvention, it is open to a person skilled in the art to routinely selectthe best order of steps with which to synthesise the intermediates, andto choose the form of the intermediate compounds which provides the bestcombination of features for this purpose. Such features include themelting point, solubility, processability and yield of the intermediateform and the resulting ease with which the product may be purified onisolation.

The skilled person may undertake the synthetic steps described below inany suitable order in order to arrive at the compounds of formula (I).

According to a first process, compounds of formula (I) may be preparedfrom compounds of formula (VI) by the process illustrated in Scheme 1.

Wherein

R^(a) is a suitable protecting group, preferably dimethoxybenzyl,tert-butyloxycarbonyl, tert-butyl, methoxymethyl or ethoxyethyl.

Compounds of formula (VI) are either commercially available or can beprepared according to Scheme 8.

Compounds of formula (III) are either commercially available or can beprepared according to Scheme 11.

Compounds of formula (VIII) and (IX) are commercially available.

Compounds of formula (IV) can be prepared from compounds of formula (VI)and (VII) according to reaction step (iii) by displacement of a sulfonylchloride with HNR^(a)Z under basic reaction conditions. Typicalconditions comprise lithium hexamethyldisilazane in THF from −78° C. toambient temperature.

Alternatively, compounds of formula (IV) can be prepared from compoundsof formula (V) according to reaction step (ii) by introduction of asuitable protecting group such as tert-butyl or methoxymethyl orethoxyethyl dimethoxybenzyl under basic reaction conditions or Mitsunobuconditions. Typical conditions comprise di-tert-butyldicarbonate andtriethylamine in THF or chloromethyl methyl ether anddiisopropylethylamine in methylene chloride or chloromethyl ethyl etherand diisopropylethylamine in methylene chloride ordimethoxybenzylalcohol, diisopropylazodicarboxylate andtriphenylphosphine in THF.

Compounds of formula (V) can be prepared from compounds of formula (VI)according to reaction step (i) by displacement of a sulfonyl chlorideunder basic reaction conditions, for example lithiumhexamethyldisilazane, diazabicyclo(2.2.2)octane, triethylamine, NaOH orpyridine. Preferred conditions comprise NaOH in 1,4-dioxane or pyridinein dichloromethane at room temperature.

Compounds of formula (II) can be prepared from compounds of formula (IV)according to reaction step (iv) by nucleophilic aromatic substitutionreaction with a phenol (III) under basic reaction conditions, forexample potassium carbonate in DMF or DMSO, sodium hydride in NMP orDMF, sodium hydroxide or potassium hydroxide in 1,4-dioxane and water orDMSO or potassium tert-butoxide in THF at from room temperature to 150°C. Preferred conditions comprise 2 equivalents of potassium carbonate inDMF at 90° C.

Compounds of formula (I) can be prepared from compounds of formula (II)according to reaction step (v) by suitable deprotection methods underacidic conditions for example HCl, formic acid or trifluoroacetic acid.Preferred methods comprise trifluoroacetic acid in dichloromethane orneat trifluoroacetic acid at a temperature of room temperature to 55° C.Alternatively, if the protecting group is dimethoxybenzyl, compounds offormula (I) can be prepared from compounds of formula (II) under basicconditions such as sodium bicarbonate in ethanol/water at 80° C. orheating in an appropriate solvent such as ethanol or toluene attemperatures exceeding 70° C.

Compounds of formula (VII) can be prepared from compounds of formula(VIII) according to reaction step (vi) by Curtius rearrangement throughgeneration of an acyl azide using diphenylphosphoryl azide. Preferredconditions comprise diphenylphosphoryl azide and triethylamine withtert-butanol in toluene at 90° C.

Alternatively compounds of formula (VII) may be prepared from compoundsof formula (IX) according to reaction step (vii) through the processesoutlined for reaction step (ii) or by reductive amination with analdehyde. Typical reaction conditions comprise dimethoxybenzaldehyde intoluene at 110° C. followed by reduction with sodium borohydride.

According to a second process, compounds of formula (I) may also beprepared from compounds of formula (V) by the process illustrated inScheme 2.

Compounds of formula (I) can be prepared from compounds of formula (V)by nucleophilic aromatic substitution reaction according to process step(iv) as described above for Scheme 1.

According to a third process, compounds of formula (I) may also beprepared from compounds of formula (XIII) by the process illustrated inScheme 3.

Compounds of formula (XIII) are commercially available.

Compounds of formula (XII) can be prepared from compounds of formula(XIII) by nucleophilic aromatic substitution reaction according toprocess step (iv) as described above for Scheme 1. Preferred conditionscomprise NaH in NMP at 0° C.

Compounds of formula (XI) can be prepared from compounds of formula(XII) by a reduction reaction according to process step (vii) forexample hydrogenation, a suitable metal reduction or use of sodiumdithionite. Preferred conditions comprise calcium chloride or ammoniumchloride in the presence of iron in ethanol/water.

Compounds of formula (X) can be prepared from compounds of formula (XI)according to process step (viii) by a Sandmeyer reaction. Typicalconditions comprise sodium nitrite in HCl, acetic acid and water,followed by sulfur dioxide in acetic acid with copper chloride at 0° C.

Compounds of formula (I) can be prepared from compounds of formula (X)by reaction according to process step (i) by displacement of a sulfonylchloride under basic reaction conditions with compounds of formula (IX)as described above for Scheme 1.

Alternatively compounds of formula (I) can be prepared from compounds offormula (X) by reaction according to process steps (iii) and (v) bydisplacement of a sulfonyl chloride under basic reaction conditions withcompounds of formula (VII) followed by a suitable deprotection step asdescribed above for Scheme 1.

According to a fourth process, compounds of formula (I) may also beprepared from compounds of formula (X) by the process illustrated inScheme 4.

Wherein LG is a suitable leaving group such as Cl, Br, I, F.

Compounds of formula (XV) are commercially available.

Compounds of formula (XIV) can be prepared from compounds of formula (X)according to process step (ix) by displacement of a sulfonyl chloridewith ammonia or a protected ammonium species such asdimethoxybenzylamine (that can be deprotected at a later stage undersuitable conditions to those skilled in the art). Typical conditionscomprise 7N NH₃ in methanol and THF at room temperature.

Compounds of formula (I) can be prepared from compounds of formula (XIV)according to reaction step (x) by displacement of a suitable leavinggroup on a heterocycle as described by Z under basic reactionconditions. Typical conditions comprise potassium carbonate in DMF.

According to a fifth process, compounds of formula (I) may also beprepared from compounds of formula (X) by the process illustrated inScheme 5.

Compounds of formula (XVI) can be prepared from compounds of formula (X)according to process step (xi) by displacement of a sulfonyl chloridewith pentafluorophenol. Typical conditions comprise pentafluorophenol,or optionally a trichlorophenol intermediate, and triethylamine indichloromethane at room temperature.

Compounds of formula (I) can be prepared from compounds of formula (XVI)by reaction according to process step (i) by displacement of apentafluorophenyl ester under basic reaction conditions with compoundsof formula (IX) as described above for Scheme 1.

Alternatively compound of formula (I) can be prepared from compounds offormula (XVI) by reaction according to process steps (iii) and (v) bydisplacement of a pentafluorophenyl ester under basic reactionconditions with compounds of formula (VII) followed by a suitabledeprotection step as described above for Scheme 1.

According to a sixth process, compounds of formula (I) may also beprepared from compounds of formula (IV) by the process illustrated inScheme 6.

Wherein

LG is a suitable leaving group as described in Scheme 4.

W can be an optionally substituted/ligated metal or boron group suitablefor cross-coupling reactions such as a trialkylstannane,dihydroxyborane, dialkoxyborane or halozinc or a suitable group forcross-coupling reactions, typically Br or I.

Compounds of formula (XVIII), (XXI) and (XX) are commercially availableor can be prepared according to Scheme 11.

Compounds of formula (XVII) can be prepared from compounds of formula(IV) according to process step (iv) by nucleophilic aromaticsubstitution reaction with compounds of formula (XVIII) as described inScheme 1.

Alternatively compounds of formula (XVII) can be prepared from compoundsof formula (IV) according to process steps (xiii) and (iv) bynucleophilic aromatic substitution with TMS-ethanol, typical conditionscomprise sodium hydride in DMF at 0° C., followed by nucleophilicaromatic substitution reaction with compounds of formula (XX) asdescribed in Scheme 1.

Compounds of formula (I) may be prepared from compounds of formula(XVII) according to process step (xii) and (v) by a cross-couplingreaction, with compounds of formula (XXI), in the presence of a suitablecatalyst system, (e.g. palladium or nickel), and base. Typically‘Suzuki’ conditions are used, comprising 1.2-3 equivalents of boronicacid, base and 0.01-0.25 equivalents of a palladium catalyst withphosphine based ligands in an organic solvent at a temperature of from50° C. to 100° C. Preferred conditions comprise boronic acid, Na₂CO₃ andPd(PPh₃)₄ in DMF/water or DME/water at 80° C. followed by a suitabledeprotection step as described in Scheme 1.

According to a seventh process, compounds of formula (I) may also beprepared from compounds of formula (V) by the process illustrated inScheme 7.

Wherein

W can be an optionally substituted/ligated metal or boron group or asuitable group for cross-coupling reactions, typically Br or I asdescribed for Scheme 6.

Compounds of formula (XXII) can be prepared from compounds of formula(V) according to process step (iv) by nucleophilic aromatic displacementreaction as described in Scheme 1.

Compounds of formula (I) can be prepared from compounds of formula(XXII) according to process step (xii) by a cross-coupling reaction,with compounds of formula (XXI), in the presence of a suitable catalystsystem as described in Scheme 6.

According to an eighth process, compounds of formula (VI) may also beprepared from compounds of formula (XXIII) by the process illustrated inScheme 8.

Compounds of formula (XXIII) are commercially available.

Compounds of formula (XXIV) can be prepared from compounds of formula(XXIII) according to process step (xiv) by nucleophilic aromaticsubstitution reaction with benzylmercaptan. Typical conditions comprisebenzylmercaptan and cesium carbonate in DMSO at room temperature.

Compounds of formula (VI) can be prepared from compounds of formula(XXIV) according to reaction step (xv), an oxidation process in thepresence of bleach. Preferred conditions comprise bleach and 4M HCl(aqueous) in dichloromethane at 0° C.

According to a ninth process, compounds of formula (X) may also beprepared from compounds of formula (XXVII) by the process illustrated inScheme 9.

Wherein

W can be an optionally substituted/ligated metal or boron group or asuitable group for cross-coupling reactions, typically Br or I asdescribed for Scheme 6.

Compounds of formula (XXVII) are commercially available.

Compounds of formula (XXVI) can be prepared from compounds of formula(XXVII) by nucleophilic aromatic substitution reaction according toprocess step (iv) as described above for Scheme 1.

Compounds of formula (XXV) can be prepared from compounds of formula(XXVI) by a palladium catalysed cross-coupling reaction withbenzylmercaptan according to process step (xvi). Typical conditionscomprise benzylmercaptan, palladium dibenzylideneacetone and xantphos in1,4-dioxane and diisopropyl ether at reflux.

Compounds of formula (X) can be prepared from compounds of formula (XXV)by an oxidation reaction according to process step (xv) as described forScheme 8.

According to a tenth process, compounds of formula (I) may also beprepared from compounds of formula (X) by the process illustrated inScheme 10.

Wherein

U and V are any suitable ring precursors such as N, NH, S, O etc.

Compounds of formula (XXIX) are commercially available.

Compounds of formula (XXVIII) can be prepared according to reaction step(i) by displacement of a sulfonyl chloride with compounds of formula(XXIX) under basic reaction conditions as described in Scheme 1. Typicalconditions comprise sodium hydroxide in acetone and water at roomtemperature.

Compounds of formula (I) can be prepared from compounds of formula(XXVIII), a cyclisation reaction according to process step (xvii).Typical conditions comprise heating at 120° C. in the presence of asuitable electrophile such as DMFDMA, trimethylorthoformate orglycoaldehyde.

According to an eleventh process, compounds of formula (III) may also beprepared from compounds of formula (XXX) by the process illustrated inScheme 11.

Compounds of formula (XXX) are commercially available or can besynthesized from methods known to one skilled in the art.

Compounds of formula (III) may be prepared from compounds of formula(XXX) by the process illustrated in Scheme 11. Where C is an aromaticheterocyclic group, compounds of formula (III) can be formed fromcompounds of formula (XXX) with R1 being a group such as a carboxylicacid, ester, aldehyde, primary carboxamide, amine, hydrazine, oxime,nitrile, hydroxylamine, acetyl, furan, dialkylaminoprop-2-ene-1-one,semicarbazone, diimine, alkyne or acid chloride using methods describedin the literature. Such literature is described and cited in text bookssuch as: Heterocyclic Chemistry, J. A. Joule and K. Mills (BlackwellScience); Handbook of Heterocyclic Chemistry, A. R. Katritzky and A. F.Pozharskii (Pergamon); The Chemistry of Heterocycles: Structure,Reactions, Syntheses and Applications, T. Eicher and S. Hauptmann(Wiley-VCH); Heterocyclic Chemistry, T. L. Gilchrist (Addison WesleyLongman).

Alternatively R1 can be an optionally substituted metal or a boron groupsuitable for cross-coupling reactions such as a trialkylstannane,dihydroxyborane, dialkoxyborane or halozinc or a suitable group forcross-coupling reactions, typically Br, I or Cl. Typical ‘Suzuki’conditions comprise of 1.2-3 equivalents of boronic acid, base and0.01-0.25 equivalents of a palladium catalyst with phosphine basedligands in an organic solvent at a temperature of from 50° C. to 100° C.Typical ‘Stine’ conditions are 1-1.5 eq stannane, 2-3 eq caesiumfluoride, 0.01-0.25 eq of a palladium catalyst and 0.1-0.25 eq copper(I) iodide.

Scheme 12

According to a twelfth process, compounds of formula (II) may also beprepared from compounds of formula (IV) by the process illustrated inScheme 12.

Wherein

LG is a suitable leaving group as described in Scheme 4.

R¹ is described in Scheme 11

Compounds of formula (XXXI) can be prepared from compounds of formula(IV) according to process step (iv) by nucleophilic aromaticsubstitution reaction with compounds of formula (XXX) as described inScheme 1.

Alternatively compounds of formula (XXXI) can be prepared from compoundsof formula (IV) according to process steps (xiii) and (iv) bynucleophilic aromatic substitution with TMS-ethanol, typical conditionscomprise sodium hydride in DMF at 0° C., followed by nucleophilicaromatic substitution reaction with compounds of formula (XXXII) asdescribed in Scheme 1.

Compounds of formula (II) may be prepared from compounds of formula(XXXI) according to standard processes described in Scheme 11.

According to a thirteenth process, compounds of formula (I) may also beprepared from compounds of formula (V) by the process illustrated inScheme 13.

Compounds of formula (XXXI) can be prepared from compounds of formula(V) according to process step (iv) by nucleophilic aromatic displacementreaction as described in Scheme 1.

Compounds of formula (I) can be prepared from compounds of formula(XXXI) according to processes described in Scheme 11.

The methods described in Schemes 12 and 13 using R1-X—B—OH in anucleophilic aromatic substitution reaction can also be used in place ofC—X—B—OH to synthesise (I) by the methods described in Schemes 3, 4 and5.

According to a fourteenth process compounds of formula (I) and (II) canbe modified through further reaction of C to change the substitution onC when C is Het1, Het2 or Ar. As an example, when C contains a primaryor secondary amino functionality, further substitution can be madethrough a simple alkyaltion or reductive alkylation procedure. Preferredconditions for the reductive alkylation include an alkyl aldhehyde,sodium triacetoxyborohydride and acetic acid in tetrahydrofuran at roomtemperature. As a further example, when C is chloropyridyl, furthersubstitution is possible through nucleophilic displacement by an aminoor alkoxy functionality.

According to a fifteenth process compounds of formula (III) when C isHet2 may be further modified to convert C into a different Het2. As anexample when C is furan, a Diels Alder with a reaction with anazadicarboxylate ester in the presence of a Lewis acid catalyst such aszinc triflate yields a bicyclic adduct. Ester hydrolysis with forexample an acid (such as acetic acid) or a base (such as sodiumhydroxide) results in decarboxylation and dehydration to yield apyridazine.

According to a sixteenth process:

compounds of formula (XXXII), which are commercially available or knownin the literature, are typically treated with chlorosulfonic acid inchloroform at 0° C. with warming to ambient temperature to providecompounds of formula (VI).

Referring to the general methods above, it will be readily understood tothe skilled person that where protecting groups are present, these willbe generally interchangeable with other protecting groups of a similarnature, e.g. where a sulfonamide is described as being protected with atert-butyl or dimethoxybenzyl group, this may be readily interchangedwith any suitable sulfonamide protecting group. Suitable protectinggroups are described in ‘Protective Groups in Organic Synthesis’ by T.Greene and P. Wuts (3^(rd) edition, 1999, John Wiley and Sons).

The present invention also relates to novel intermediate compounds asdefined above, all salts, solvates and complexes thereof and allsolvates and complexes of salts thereof as defined hereinbefore forcompounds of formula (I). The invention includes all polymorphs of theaforementioned species and crystal habits thereof.

EXAMPLES & PREPARATIONS

The following experimental details illustrate specifically how certaincompounds of formula (I) may be prepared. All examples, unless indicatedas a reference example, are compounds of formula (I). Preparations areintermediates useful in the synthesis of compounds of formula (I).

¹H Nuclear magnetic resonance (NMR) spectra were in all cases consistentwith the proposed structures. Characteristic chemical shifts (δ) aregiven in parts-per-million downfield from tetramethylsilane usingconventional abbreviations for designation of major peaks: e.g. s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.

The mass spectra (m/z) were recorded using either electrosprayionisation (ESI) or atmospheric pressure chemical ionisation (APCI).When relevant, and unless stated otherwise, the m/z data provided arefor isotopes ¹⁹F, ³⁵Cl and ⁷⁹Br.

The following abbreviations have been used for common solvents: CDCl₃,deuterochloroform; d₆-DMSO, deuterodimethylsulphoxide; CD₃OD,deuteromethanol; THF, tetrahydrofuran. ‘Ammonia’ refers to aconcentrated solution of ammonia in water possessing a specific gravityof 0.88.

Where thin layer chromatography (TLC) has been used it refers to silicagel TLC using silica gel 60 F₂₅₄ plates, R_(f) is the distance travelledby a compound divided by the distance travelled by the solvent front ona TLC plate.

Where compounds are purified by HPLC the following methods are used:

Preparative Reverse Phase HPLC Methods:

a) Phenomenex 250×30 mm 15 micron C18 column. 40 mL/minutes. Gradient85% A to 100% B over 25 minutes. Solvent A: 7800 water/200acetonitrile/8 trifluoroacetic acid. Solvent B: 7200 acetonitrile/800water/8 trifluoroacetic acid, 254 nM UV detection.

b) Phenomenex 100×21.2 mm 10 micron C18 column. 20 mL/minutes. Gradient85% A to 100% B over 25 minutes. Solvent A: 7800 water/200acetonitrile/8 trifluoroacetic acid. Solvent B: 7200 acetonitrile/800water/8 trifluoroacetic acid, 254 nM UV detection.

Certain compounds of the Examples and Preparations were purified usingAutomated Preparative High Performance Liquid Chromatography (HPLC).Reversed-phase HPLC conditions were on FractionLynx systems. Sampleswere submitted dissolved in 1 mL of DMSO. Depending on the nature of thecompounds and the results of a pre-analysis, the purification wasperformed under either acidic conditions or basic conditions at ambienttemperature. Acidic runs were carried out on a Sunfire Prep C18 OBDcolumn (19×50 mm, 5 μm), basic runs were carried out on a Xterra Prep MSC18 (19×50 mm, 5 μm), both from Waters. A flow rate of 18 mL/minutes wasused with mobile phase A: water+0.1% modifier (v/v) and B:acetonitrile+0.1% modifier (v/v). For acidic runs the modifier wasformic acid, for basic run the modifier was diethylamine. A Waters 2525binary LC pump supplied a mobile phase with a composition of 5% B for 1minutes then ran from 5% to 98% B over 6 minutes followed by a 2 minuteshold at 98% B.

Detection was achieved using a Waters 2487 dual wavelength absorbancedetector set at 225 nm followed in series by a Polymer Labs PL-ELS 2100detector and a Waters ZQ 2000 4 way MUX mass spectrometer in parallel.The PL 2100 ELSD was set at 30° C. with 1.6 L/minutes supply ofNitrogen. The Waters ZQ MS was tuned with the following parameters:

ES+ Cone voltage: 30 v Capillary: 3.20 kv

ES− Cone voltage: −30 v Capillary: −3.00 kv

Desolvation gas: 600 L/hour

Source Temp: 120° C.

Scan range 150-900 Da

The fraction collection was triggered by both MS and ELSD.

Quality control analysis was performed using a LCMS method orthogonal tothe preparative method. Acidic runs were carried out on a Sunfire C18(4.6×50 mm, 5 μm), basic runs were carried out on a Xterra C18 (4.6×50mm, 5 μm), both from Waters. A flow rate of 1.5 mL/minutes was used withmobile phase A: water+0.1% modifier (v/v) and B: acetonitrile+0.1%modifier (v/v). For acidic runs the modifier was formic acid, for basicrun the modifier was diethylamine. A Waters 1525 binary LC pump ran agradient elution from 5% to 95% B over 3 minutes followed by a 1 minuteshold at 95% B. Detection was achieved using a Waters MUX UV 2488detector set at 225 nm followed in series by a Polymer Labs PL-ELS 2100detector and a Waters ZQ 2000 4 way MUX mass spectrometer in parallel.The PL 2100 ELSD was set at 30° C. with 1.6 L/minutes supply ofNitrogen. The Waters ZQ MS was tuned with the following parameters:

ES+Cone voltage: 25 v Capillary: 3.30 kv

ES−Cone voltage: −30 v Capillary: −2.50 kv

Desolvation gas: 800 L/hour

Source Temp: 150° C.

Scan range 160-900 Da

Unless otherwise noted, LCMS conditions were run according to one of theconditions given below:

6 minute LC-MS Gradient and Instrument Conditions

Acid Run:

A: 0.1% formic acid in water

B: 0.1% formic acid in acetonitrile

Column: C18 phase Phenomenex Gemini 50×4.6 mm with 5 micron particlesize

Gradient: 95-5% A over 3 min, 1 minutes hold, 1 ml/minutes

UV: 210 nm-450 nm DAD

Temperature: 50 C

2 minute LC-MS Gradient and Instrument Conditions

Acid Run:

A: 0.1% formic acid in water

B: 0.1% formic acid in acetonitrile

Column: C18 phase Fortis Pace 20×2.1 mm with 3 micron particle size

Gradient: 70-2% A over 1.8 min, 0.2 minutes hold, 1.8 ml/minutes

UV: 210 nm-450 nm DAD

Temperature: 75 C

C18 30 Minute Method LC-MS Gradient and Instrument Conditions

A: 0.1% formic acid in H2O

B: 0.1% formic acid in MeCN

Column: Phenomenex C18 phase Gemini 150×4.6 mm with 5 micron particlesize

Gradient: 98-2% A over 18 min, 2 minutes hold, 1 ml/minutes

UV: 210 nm-450 nm DAD

Temperature: 50 C

Phenyl Hexyl 30 Minute Method LC-MS Gradient and Instrument Conditions

A: 10 mM ammonium acetate in H2O

B: 10 mM ammonium acetate in methanol

Column: Phenomenex Phenyl Hexyl 150×4.6 mm with 5 micron particle size

Gradient: 98-2% A over 18 min, 2 minutes hold, 1 ml/minutes

UV: 210 nm-450 nm DAD

Temperature: 50 C

Unless otherwise provided herein:

AcOH means acetic acid,

Boc means tert-butoxycarbonyl; (tert-butyloxycarbonyl) WSCDI means1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

CBz means benzyloxycarbonyl;

CDI means N,N′-carbonyldiimidazole;

DABCO means 1,4-diazabicyclo[2.2.2]octane

DCC means N,N′-dicyclohexylcarbodiimide;

DCM means dichloromethane; methylene chloride;

DMAP means 4-dimethylaminopyridine;

DMB means dimethoxybenzyl;

DME means dimethoxylethane;

DMF means N,N-dimethylformamide;

DMFDMA means N,N-dimethylformamide dimethylacetal

DMSO means dimethyl sulphoxide;

Et₃N means triethylamine;

EtOH means ethanol

HBTU means O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate;

HCl means hydrochloric acid;

HOAT means 1-hydroxy-7-azabenzotriazole;

HOBT means 1-hydroxybenzotriazole hydrate;

Hünig's base means N-ethyldiisopropylamine;

K₂CO₃ means potassium carbonate;

KOH means potassium hydroxide;

LiHMDS means lithium bis(trimethylsilyl)amide;

Me means methyl;

NaH means sodium hydride;

Na₂CO₃ means sodium carbonate;

NaOH means sodium hydroxide;

NH₃ means ammonia;

NMP means N-methylpyrrolidinone;

Pd(PPh₃)₄ means palladium tetrakis;

Pd₂(dba)₃ means Tris(dibenzylideneacetone)dipalladium;

TBTU means O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate;

TFA means trifluoroacetic acid;

THF means tetrahydrofuran; and

TMS means trimethylsilyl.

Example 13-cyano-4-(4-fluoro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Method A

To a suspension of sodium hydride (60% dispersion in oil, 0.062 g) inN,N-dimethylformamide (5 mL) was added4-fluoro-2-(1-methyl-1H-pyrazol-5-yl)phenol (Preparation 88A, 0.072 g,0.00037 mol). This was stirred at room temperature for 10 minutes. Tothis mixture was added3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(Preparation 65, 0.103 g, 0.000362 mol) and the resulting mixture wasstirred for 3 hours. The reaction was quenched with 1N HCl (aq) andextracted twice with ethyl acetate. The combined organic layers weredried over sodium sulfate, filtered, and concentrated in vacuo. Theresulting residue was purified by flash column chromatography using agradient of 0-10% methanol in CH₂Cl₂ to give the title compound as awhite solid. LCMS Rt=1.50 minutes MS m/z 457.0 [MH]+

Example 22-fluoro-4-(2-(2-methylthiazol-4-yl)phenoxy)-N-(thiazol-2-yl)benzenesulfonamide)

Method B

To a suspension of sodium hydride (60% dispersion in oil, 0.0260 g) inN,N-dimethylformamide (5 mL) was added 2-(2-methylthiazol-4-yl)phenol(0.0830 g, 0.000434 mol). This was stirred at 20° C. for 10 minutes andthen cooled to 5° C. in an ice water bath. To this mixture was addedN-tert-butyl-2,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide(Preparation 62, 0.151 g, 0.000454 mol) and the reaction was allowed toslowly warm to room temperature. After stirring for 16 hours, thereaction was quenched with water and extracted twice with ethyl acetate.The combined organic layers were dried over sodium sulphate, filtered,and concentrated in vacuo. The resulting residue was purified by flashcolumn chromatography. The purified product was dissolved in methylenechloride (15 mL) and treated with trifluoroacetic acid (5 mL, 0.06 mol).After stirring for 30 minutes, the reaction was concentrated in vacuoand the residue purified by flash column chromatography using a gradientof 0-5% methanol in CH₂Cl₂, providing the title compound as a whitesolid. LCMS Rt=1.54 minutes MS m/z 447.8 [MH]+

Example 33-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)phenoxy)-N-(thiazol-2-yl)benzenesulfonamide

Method C

To a suspension of sodium hydride (60% dispersion in oil, 52 mg, 0.0013mol) in DMF (1 mL) was added 2-(1-methyl-1H-pyrazol-5-yl)phenol(Preparation 92A, 176 mg, 0.00101 mol) as a solution in DMF (1 mL) andthe mixture was stirred for 15 minutes. To this was addedN-tert-butyl-3,4-difluoro-N-thiazol-2-yl-benzenesulfonamide (Preparation60, 350 mg, 0.00105 mol) as a solution in DMF (1 mL). The resultingorange solution was heated at 80° C. for 3 days. After cooling thereaction was diluted with ethyl acetate and washed with saturatedaqueous NaHCO₃, water, and brine. The organic layer was dried overMgSO₄, filtered, and concentrated in vacuo. The crude product waspurified by flash column chromatography using a 0-100% ethyl acetate inhexanes gradient to give a clear oil. This was dissolved intrifluoroacetic acid (3 mL, 0.04 mol) and heated to 50° C. for 24 h.After cooling, the reaction was concentrated in vacuo and purified byflash column chromatography using a 0-10% methanol in CH₂Cl₂ gradient togive the title compound as a white solid. LCMS Rt=1.49 minutes MS m/z430.9 [MH]+

Example 43-cyano-4-[(4′-isopropoxy-2′-methylbiphenyl-2-yl)oxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

Method D

To a solution of 4′-isopropoxy-2′-methyl-biphenyl-2-ol (Preparation 37,51 mg, 0.212 mmol) and KOH (17.8 mg, 0.318 mmol) in DMSO (1 mL) wasadded 3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(Preparation 65, 30 mg, 0.11 mmol). The mixture was stirred at roomtemperature overnight followed by stirring at 60° C. for 24 h. 2N HCl(aq) (5 ml) was added to the reaction mixture followed by extractioninto tert-butyl methyal ether (10 ml). The organic layer was collected,dried (MgSO4) and concentrated in vacuo to afford the crude compoundwhich was purified using silica gel column chromatography(dichloromethane:methanol 95:5) to furnish the title compound. LCMSRt=3.38 minutes MS m/z 507 [MH]+

Example 53-cyano-4-[(5-fluoro-3′-isopropoxybiphenyl-2-yl)oxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

Method E

To a solution of4-(2-bromo-4-fluoro-phenoxy)-3-cyano-N-[1,2,4]thiadiazol-5-ylbenzenesulfonamide(Preparation 44, 72.6 mg, 0.15 mmol) in DMF (0.8 mL) was added3-isopropoxyphenylboronic acid (40 mg, 0.225 mmol), palladium tetrakistriphenylphosphine (8.10 mg, 0.007 mmol) and a 2M aqueous solution ofsodium carbonate (0.225 mL, 0.45 mmol). The reaction was heated to 100°C. overnight. After cooling to room temperature, saturated aqueousammonium chloride (3 mL) and dichloromethane (3 mL) was added and theorganic extracted into dichloromethane (3×3 mL). The organic layer wasconcentrated in vacuo and the title compound purified by preparativeHPLC. LCMS Rt=2.46 minutes MS m/z 511 [MH]+

Example 63-cyano-4-(2-cyclopropyl-4-fluorophenoxy)-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

Method F

To a solution of 2-cyclopropyl-4-fluorophenol (US2005245519, 60 mg, 0.4mmol) and potassium carbonate (82.9 mg, 0.6 mmol) in DMF (1 ml) wasadded 3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(Preparation 65, 57 mg, 0.2 mmol). The reaction was heated to 80-100° C.overnight. Saturated aqueous ammonium chloride and dichloromethane wereadded to the cooled reaction and the organics extracted intodichloromethane (3×3 ml). The organic layer was dried (MgSO4) andconcentrated in vacuo to furnish the crude residue that was purifiedusing preparative HPLC. LCMS Rt=2.29 minutes MS m/z 417 [MH]+

Example 954-(biphenyl-2-yloxy)-3-cyano-N-1,3-oxazol-2-ylbenzenesulfonamide

Method G

Triethylamine (38 ul, 0.27 mmol) was added to oxazol-2-ylamine (14 mg,0.169 mmol) in THF (0.5 ml) and stirred for 5 minutes.4-(biphenyl-2-yloxy)-3-cyano-benzenesulfonyl chloride (Preparation 55,50 mg, 0.14 mmol) in THF (0.5 ml) was then added slowly and the reactionstirred at room temperature overnight. Aqueous 2N HCl was added and thereaction extracted into ethyl acetate three times, the organic layercollected, dried (MgSO4), and concentrated in vacuo to furnish a cruderesidue that was purified using preparative HPLC. LCMS Rt=3.17 minutesMS m/z 418 [MH]+

Example 964-(biphenyl-2-yloxy)-3-cyano-N-(3-methoxy-1,2,4-thiadiazol-5-yl)benzenesulfonamide

Method H

NaOH (8 mg, 0.203 mmol) in water (0.25 ml) was added to3-methoxy-[1,2,4]-thiadiazol-5-ylamine (27 mg, 0.203 mmol) in1,4-dioxane (1.0 ml) and stirred at ambient temperature for 5 minutes.4-(Biphenyl-2-yloxy)-3-cyano-benzenesulfonyl chloride (Preparation 55,50 mg, 0.14 mmol) in 1,4-dioxane (0.5 ml) was added slowly and stirringcontinued at ambient temperature overnight. Aqueous HCl solution (2M,0.2 ml) was added, then saturated brine (2 ml), and the mixtureextracted with ethyl acetate (3×2 ml). The combined organic layers werecollected, dried (MgSO4), and concentrated in vacuo to furnish a cruderesidue that was purified using preparative HPLC.

LCMS Rt=2.49 min MS m/z 464.9 [MH]+

Example 974-(biphenyl-2-yloxy)-3-cyano-N-1,3-thiazol-4-ylbenzenesulfonamide

Method I

4-(Biphenyl-2-yloxy)-3-cyano-benzenesulfonyl chloride (Preparation 55,50 mg, 0.14 mmol) in MeCN (0.5 ml) was added dropwise tothiazol-4-ylamine (20 mg, 0.15 mmol) and DABCO (34 mg, 0.297 mmol) inMeCN (0.5 ml) and the heterogeneous mixture stirred together at 70° C.for 24 h. The reaction was concentrated in vacuo and the residue wastaken up in methanol (5 ml), passed through pad of charcoal and Celite™,and washed with methanol. The filtrate was concentrated in vacuo toafford a crude residue that was purified using preparative HPLC. LCMSRt=3.72 min MS m/z 433.9 [MH]+

Example 984-(biphenyl-2-yloxy)-3-cyano-N-(3-isopropyl-1,2,4-thiadiazol-5-yl)benzenesulfonamide

Method J

LiHMDS (1M solution in THF, 194 ul, 0.194 mmol) was added to a stirredsolution of 3-isopropyl-[1,2,4]thiadiazol-5-ylamine (28 mg, 0.194 mmol)in THF (0.5 ml). 4-(biphenyl-2-yloxy)-3-cyano-benzenesulfonic acidpentafluorophenyl ester (Preparation 58, 50 mg, 0.097 mmol) was addedand the reaction was heated to 50° C. overnight. The reaction was cooledand concentrated in vacuo before being purified using preparative HPLC.

LCMS Rt=3.88 min MS m/z 477 [MH]+

Example 994-(biphenyl-2-yloxy)-3-cyano-N-isothiazol-4-ylbenzenesulfonamide

Method K

To a solution of isothiazol-4-ylamine (40 mg, 0.293 mmol) in pyridine(0.5 ml) and dichloromethane (0.5 ml) was added4-(biphenyl-2-yloxy)-3-cyano-benzenesulfonyl chloride (Preparation 55,60 mg, 0.16 mmol) and the reaction stirred at room temperatureovernight. 2N HCl was added and the reaction extracted intodichloromethane. The organic layer was collected, dried (MgSO₄) andconcentrated in vacuo to furnish a crude residue that was purified usingpreparative HPLC.

LCMS Rt=3.75 minutes MS m/z 434 [MH]+

Example 134N-(5-chloro-1,3-thiazol-2-yl)-3-cyano-4-(2-phenoxyphenoxy)benzenesulfonamide

Method L

To a solution ofN-(5-chloro-thiazol-2-yl)-3-cyano-4-fluorobenzenesulfonamide(Preparation 52, 0.2 mmol, 63.5 mg) and 2-phenoxyphenol (74 mg, 0.4mmol) in THF (1 mL) was added t-BuOK in THF (1 M, 0.6 mL). The reactionwas heated at 50° C. overnight. The reaction was cooled to roomtemperature and poured into saturated aqueous NH₄Cl. The mixture wasextracted thrice with CH₂Cl₂ and the combined organic layer was driedover MgSO₄ followed by evaporation in vacuo to obtain the crude residuewhich was purified using preparative HPLC to afford the title compound.

LCMS Rt=3.66 minutes MS m/z 484 [M³⁵ClH]+, 486 [M³⁷ClH]+

Example 1704-[4-Chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]-3-cyano-N-1,3-thiazol-2-ylbenzenesulfonamide

3-Cyano-4-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide, (Preparation 46,500 mg, 0.00176 mol), 4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenol,(Preparation 89, 370 mg, 0.00177 mol) and potassium carbonate (700 mg,0.00287 mol) were stirred in dimethylformamide (5 mL) at 80° C. for 24hours. The reaction mixture was cooled and partitioned between ethylacetate (150 mL) and aqueous hydrochloric acid (80 mL of 2 molar), theorganic layer was dried over anhydrous sodium sulphate, filtered and thesolvents removed in vacuo to give an orange solid. The solid wastriturated with diethyl ether (20 mL) to give the title compound as anorange powder, (680 mg).

LCMS=1.40 minutes, MS m/z=472 [M³⁵CIH]+

¹HNMR (d₆-DMSO): δ 3.73 (s, 3H), 6.20 (d, 1H), 6.88 (d, 1H), 6.93 (d,1H), 7.29 (d, 1H), 7.33 (d, 1H), 7.49 (d, 1H), 7.66-7.71 (m, 2H),7.87-7.91 (m, 1H), 8.10 (d, 1H).

Example 2794-[4-(2-tertbutyl-5-trifluoromethyl-2H-pyrazol-3-yl)-phenoxy]-3-cyano-N-thiazol-2-yl-benzenesulfonamide

Method M

3-Cyano-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide (Preparation 46, 89mg, 0.31 mmol) was added to a mixture of4-(2-tert-butyl-5-trifluoromethyl-2H-pyrazol-3-yl)-phenol (Preparation190, 89 mg, 0.31 mmol) and potassium carbonate (130 mg, 0.94 mmol) inN,N-dimethylformamide (2 mL, 30 mmol). The reaction mixture was heatedat 150° C. in the microwave for 2 hours. The reaction mixture wasdiluted with ethyl acetate, washed with water and brine, dried overanhydrous sodium sulfate, filtered and was concentrated to give thecrude product that was purified via automated flash chromatography(silica gel, 0% to 80% ethyl acetate in hexanes). 114 mg (66%) of theproduct was obtained as a white solid. LCMS Rt=1.80 minutes; MS m/z 548[MH]+ ¹H NMR (300 MHz, d₆-DMSO): δ 1.46 (s, 9H), 6.73 (s, 1H), 6.92 (d,J=4.6 Hz, 1H), 7.14 (d, J=8.9 Hz, 1H), 7.34 (d, J=4.6 Hz, 1H), 7.38 (m,2H), 7.61 (m, 2H), 8.10 (dd, J=8.9 & 2.2 Hz, 1H), 8.28 (d, J=2.2 Hz,1H), 12.95 (s, br, 1H).

Library Protocol 1

To a solution of the phenol (100 μmol) in dimethylsulphoxide (1 ml) wasadded NaH (60% dispersion in oil, 8 mg, 200 μmol) and the reactionshaken at 30° C. for 1 hourr. The reaction mixture was cooled to 5° C.and a solution ofN-tert-butyl-3,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide(Preparation 60, 100 μmol) in dimethylsulphoxide (100 μl) was addedfollowed by continued shaking at 70° C. for 16 hours. The crude productwas purified by preparative HPLC to yield pure intermediate. 1 ml of atrifluoroacetic acid/dichloromethane solution (1:7) was added to theintermediate and the reaction shaken at 30° C. for 1 hour. The reactionwas concentrated in vacuo to yield the desired product.

The following further examples can be prepared analogously to theGeneral Methods (as described above), and Methods A-M, as described forExamples 1-6, 95-99, 134, and 279, and Library protocol 1, substitutingappropriate starting materials where necessary and making appropriatechanges to experimental conditions informed by common general knowledge.Purification was performed either by silica gel column chromatography,trituration or preparative HPLC.

MS m/z Eg (unless otherwise No Name indicated) 73-cyano-4-{[2-(4-ethylphenyl)pyridin-3- 464 [MH]+yl]oxy}-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 83-cyano-4-{[2-(dimethylamino)-4-(4- 498 [MH]+fluorophenyl)pyrimidin-5-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 9 3-cyano-4-{[2-(dimethylamino)-4-(4-494 [MH]+ methylphenyl)pyrimidin-5-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 103-cyano-4-[(4′-methoxy-2′-methylbiphenyl-2- 479 [MH]+yl)oxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 113-cyano-4-[(4′-cyanobiphenyl-2-yl)oxy]-N- 460 [MH]+1,2,4-thiadiazol-5-ylbenzenesulfonamide 123-cyano-4-[(6-methyl-2-phenylpyridin-3- 450 [MH]+yl)oxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 133-cyano-4-[(4′-cyano-3′-methoxybiphenyl-2- 490 [MH]+yl)oxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 143-cyano-4-{[2-(dimethylamino)-4-(2- 498 [MH]+fluorophenyl)pyrimidin-5-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 153-cyano-4-[(4′-isopropoxy-3-methylbiphenyl- 505 [MH]−2-yl)oxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 163-cyano-4-{[4-(4-fluorophenyl)-2- 482 [MH]−(methylamino)pyrimidin-5-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 173-cyano-4-{[2-(4-methylphenyl)pyridin-3- 450 [MH]+yl]oxy}-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 184-{[2-amino-4-(4-chlorophenyl)pyrimidin-5- 484 [MH]−yl]oxy}-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 193-cyano-4-[(6-ethyl-2-phenylpyridin-3- 464 [MH]+yl)oxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 203-cyano-4-[(3-phenylpyrazin-2-yl)oxy]-N- 437 [MH]+1,2,4-thiadiazol-5-ylbenzenesulfonamide 213-cyano-4-[(4-phenylpyridazin-3-yl)oxy]-N- 437 [MH]+1,2,4-thiadiazol-5-ylbenzenesulfonamide 223-cyano-4-[(2-phenylpyridin-3-yl)oxy]-N- 436 [MH]+1,2,4-thiadiazol-5-ylbenzenesulfonamide 234-[(2-amino-4-phenylpyrimidin-5-yl)oxy]-3- 452 [MH]+cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 244-(biphenyl-2-yloxy)-3-cyano-N-(1,2,4- 435 [MH]+thiadiazol-5-yl)benzenesulfonamide 254-(4-chloro-2-(1-methyl-1H-pyrazol-5- 473 [M³⁵ClH]+yl)phenoxy)-3-cyano-N-(1,2,4-thiadiazol-5- yl)benzenesulfonamide 263-cyano-4-(4-fluoro-2-(1-(2,2,2- 525 [MH]+trifluoroethyl)-1H-pyrazol-5-yl)phenoxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide 273-cyano-4-(2-(1,4-dimethyl-1H-pyrazol-5-yl)- 467 [MH]+4-methylphenoxy)-N-(1,2,4-thiadiazol-5- yl)benzenesulfonamide 283-cyano-4-(2-(1,4-dimethyl-1H-pyrazol-3-yl)- 467 [MH]+4-methylphenoxy)-N-(1,2,4-thiadiazol-5- yl)benzenesulfonamide 29 ethyl2-(5-(2-(4-(N-1,2,4-thiadiazol-5- 545 [M³⁵ClH]+ylsulfamoyl)-2-cyanophenoxy)-5- chlorophenyl)-1H-pyrazol-1-yl)acetate 30methyl 4-(4-(N-1,2,4-thiadiazol-5- 497.2 [MH]+ylsulfamoyl)-2-cyanophenoxy)-3-(1-methyl- 1H-pyrazol-5-yl)benzoate 313-cyano-4-[(2′,5′-difluoro-3-methylbiphenyl-2- 485 [MH]+yl)oxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 323-cyano-4-[(3′-isopropoxy-3-methylbiphenyl- 507 [MH]+2-yl)oxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 333-cyano-N-1,2,4-thiadiazol-5-yl-4-[(2′,5,5′- 489 [MH]+trifluorobiphenyl-2- yl)oxy]benzenesulfonamide 343-cyano-4-[(3′-isopropoxybiphenyl-2-yl)oxy]- 493 [MH]+N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 353-cyano-4-[(2′,4′-difluoro-3-methylbiphenyl-2- 485 [MH]+yl)oxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 363-cyano-4-[(2′,5′-difluorobiphenyl-2-yl)oxy]- 471 [MH]+N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 37 3-cyano-4-{[3-methyl-3′-533 [MH]+ (trifluoromethoxy)biphenyl-2-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 383-cyano-4-[(3′-fluoro-3-methylbiphenyl-2- 467 [MH]+yl)oxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 393-cyano-4-[(4′-fluoro-3-methylbiphenyl-2- 467 [MH]+yl)oxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 403-cyano-4-{[3-methyl-4′- 533 [MH]+(trifluoromethoxy)biphenyl-2-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 413-cyano-4-[(3′-fluoro-4′-methoxy-3- 497 [MH]+methylbiphenyl-2-yl)oxy]-N-1,2,4-thiadiazol- 5-ylbenzenesulfonamide 423-cyano-4-[(4′-methoxy-3-methylbiphenyl-2- 479 [MH]+yl)oxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 433-cyano-4-[(2′-fluoro-3-methylbiphenyl-2- 467 [MH]+yl)oxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 443-cyano-4-[(3′,4′-difluoro-3-methylbiphenyl-2- 485 [MH]+yl)oxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 453-cyano-4-[(3′,5′-difluoro-3-methylbiphenyl-2- 485 [MH]+yl)oxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 463-cyano-N-1,2,4-thiadiazol-5-yl-4-[(2′,4′,5- 489 [MH]+trifluorobiphenyl-2- yl)oxy]benzenesulfonamide 473-cyano-4-[(3′-fluorobiphenyl-2-yl)oxy]-N- 451 [MH]−1,2,4-thiadiazol-5-ylbenzenesulfonamide 483-cyano-4-[(3′-fluoro-4′-methoxybiphenyl-2- 483 [MH]+yl)oxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 493-cyano-4-[(4′-fluorobiphenyl-2-yl)oxy]-N- 453 [MH]+1,2,4-thiadiazol-5-ylbenzenesulfonamide 503-cyano-4-[(2′-fluorobiphenyl-2-yl)oxy]-N- 453 [MH]+1,2,4-thiadiazol-5-ylbenzenesulfonamide 513-cyano-4-[(4′-methoxybiphenyl-2-yl)oxy]-N- 465 [MH]+1,2,4-thiadiazol-5-ylbenzenesulfonamide 523-cyano-4-[(3′,4′-difluorobiphenyl-2-yl)oxy]- 471 [MH]+N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 533-cyano-4-[(3′,5′-difluorobiphenyl-2-yl)oxy]- 471 [MH]+N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 543-cyano-4-[(4′-isopropoxybiphenyl-2-yl)oxy]- 493 [MH]+N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 553-cyano-N-1,2,4-thiadiazol-5-yl-4-{[3′- 519 [MH]+(trifluoromethoxy)biphenyl-2- yl]oxy}benzenesulfonamide 563-cyano-4-[(2′,4′-difluorobiphenyl-2-yl)oxy]- 471 [MH]+N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 573-cyano-N-1,2,4-thiadiazol-5-yl-4-{[4′- 519 [MH]+(trifluoromethoxy)biphenyl-2- yl]oxy}benzenesulfonamide 583-cyano-4-{[1-(2,4-difluorophenyl)-3- 529 [MH]+(trifluoromethyl)-1H-pyrazol-5-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 593-cyano-4-{[1-(3,4-difluorophenyl)-3- 529 [MH]+(trifluoromethyl)-1H-pyrazol-5-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 603-cyano-4-[4-(cyclopropylmethyl)phenoxy]-N- 413 [MH]+1,2,4-thiadiazol-5-ylbenzenesulfonamide 614-[4-(azetidin-1-ylmethyl)-2-fluorophenoxy]- 446 [MH]+3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 623-cyano-4-[2-(3,5-dimethyl-1H-pyrazol-4- NMR Data was:yl)phenoxy]-N-1,2,4-thiadiazol-5- ¹HNMR (d₆- ylbenzenesulfonamide DMSO):δ 2.05 (s, 6H), 6.59 (d, 1H), 7.33-7.55 (m, 4H), 7.84- 7.94 (m, 1H),8.06-8.15 (m, 1H), 8.47 (s, 1H). 633-cyano-4-[2-(pyridin-4-yloxy)phenoxy]-N- 452 [MH]+1,2,4-thiadiazol-5-ylbenzenesulfonamide 644-{[4-(4-chlorophenyl)-1-methyl-1H-pyrazol- 473 [M³⁵ClH]+3-yl]oxy}-3-cyano-N-1,2,4-thiadiazol-5- 475 [M³⁷ClH]+ylbenzenesulfonamide 65 3-cyano-4-{[3-isopropyl-1-(4- 497 [MH]+methoxyphenyl)-1H-pyrazol-4-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 664-[(1-benzyl-4-methyl-1H-pyrazol-3-yl)oxy]- 453 [MH]+3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 674-{[1-(2-chlorophenyl)-3-isopropyl-1H- 501 [M³⁵ClH]+pyrazol-4-yl]oxy}-3-cyano-N-1,2,4-thiadiazol- 503 [M³⁷ClH]+5-ylbenzenesulfonamide 68 3-cyano-4-(2-phenoxyphenoxy)-N-1,2,4- 451[MH]+ thiadiazol-5-ylbenzenesulfonamide 693-cyano-4-[2-(1-methyl-5-oxopyrrolidin-2- 456 [MH]+yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 703-cyano-4-[2-(1-methyl-1H-pyrazol-5- 439 [MH]+yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 713-cyano-4-[2,4-dichloro-6-(1-methyl-1H- 507 [M³⁵ClH]+pyrazol-5-yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 723-cyano-4-[2-(1-ethyl-3,5-dimethyl-1H- 481 [MH]+pyrazol-4-yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 733-cyano-4-[2,4-difluoro-6-(1-methyl-1H- 475 [MH]+pyrazol-5-yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 743-cyano-4-(5-fluoro-2-phenoxyphenoxy)-N- 469 [MH]+1,2,4-thiadiazol-5-ylbenzenesulfonamide 753-cyano-4-[2-fluoro-6-(2-methoxy-4- 513 [MH]+methylphenoxy)phenoxy]-N-1,2,4-thiadiazol- 5-ylbenzenesulfonamide 762-(2-{2-cyano-4-[(1,2,4-thiadiazol-5-yl- 494 [MH]+amino)sulfonyl]phenoxy}phenoxy)benzamide 773-cyano-4-[2-(4-fluorophenoxy)phenoxy]-N- 469 [MH]+1,2,4-thiadiazol-5-ylbenzenesulfonamide 783-cyano-4-[2-(4-cyanophenoxy)-5- 490 [MH]+methylphenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 794-(4-chloro-2-phenoxyphenoxy)-3-cyano-N- 485 [M³⁵ClH]+1,2,4-thiadiazol-5-ylbenzenesulfonamide 487 [M³⁷ClH]+ 804-{[1-benzyl-3-(trifluoromethyl)-1H-pyrazol- 507 [MH]+5-yl]oxy}-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 813-cyano-4-{[1-phenyl-3-(trifluoromethyl)-1H- 493 [MH]+pyrazol-5-yl]oxy}-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 823-cyano-4-[(1-methyl-3-phenyl-1H-pyrazol-5- 439 [MH]+yl)oxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 834-[2-(1-tert-butyl-1H-pyrazol-5-yl)-3- 499 [MH]+fluorophenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 844-[2-(1-tert-Butyl-1H-pyrazol-3-yl)-3-fluoro- 499 [MH]+phenoxy]-3-cyano-N-[1,2,4]thiadiazol-5-yl- benzene-sulfonamide 853-Cyano-4-[3-fluoro-2-(1-methyl-1H-pyrazol- 457 [MH]+3-yl)-phenoxy]-N-[1,2,4]thiadiazol-5-yl- benzene-sulfonamide 863-cyano-4-[3-fluoro-2-(1-methyl-1H-pyrazol- 457 [MH]+5-yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 873-cyano-4-{[3-cyclopropyl-1-(2,5- 501 [MH]+difluorophenyl)-1H-pyrazol-5-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 883-cyano-4-{[1-(2-fluorophenyl)-3- 511 [MH]+(trifluoromethyl)-1H-pyrazol-5-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 893-cyano-4-[3-fluoro-2-(2H-pyrazol-3-yl)- 443 [MH]+phenoxy]-N-[1,2,4]thiadiazol-5-yl- benzenesulfonamide 904-(4-chloro-2-(1-(2-hydroxyethyl)-1H-pyrazol- 503 [M³⁵ClH]+5-yl)phenoxy)-3-cyano-N-(1,2,4-thiadiazol-5- yl)benzenesulfonamide 913-cyano-4-(4-(hydroxymethyl)-2-(1-methyl- 469 [MH]+1H-pyrazol-5-yl)phenoxy)-N-(1,2,4-thiadiazol- 5-yl)benzenesulfonamide 923-(4-chloro-benzyl)-5-{2-cyano-4-(1,2,4- 559 [M³⁵ClH]+thiadiazol-5-ylsulfamoyl)-phenoxy}-pyrazol- 1-yl-acetic acid ethyl ester93 2-[3-(4-chlorobenzyl)-5-{2-cyano-4-[(1,2,4- 530 [M³⁵ClH]+thiadiazol-5-ylamino)sulfonyl]phenoxy}-1H- pyrazol-1-yl]acetamide 944-{[3-(4-chlorobenzyl)-1-(2-hydroxyethyl)- 517 [M³⁵ClH]+1H-pyrazol-5-yl]oxy}-3-cyano-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide100 4-(biphenyl-2-yloxy)-3-cyano-N-(5-methyl- 448 [MH]+1,3-thiazol-2-yl)benzenesulfonamide 1014-(biphenyl-2-yloxy)-3-cyano-N-(4-methyl- 448 [MH]+1,3-thiazol-2-yl)benzenesulfonamide 1024-(biphenyl-2-yloxy)-3-cyano-N-(3-ethyl- 463 [MH]+1,2,4-thiadiazol-5-yl)benzenesulfonamide 1034-(biphenyl-2-yloxy)-3-cyano-N-(3-methyl- 449 [MH]+1,2,4-thiadiazol-5-yl)benzenesulfonamide 1044-(biphenyl-2-yloxy)-3-cyano-N-1,3,4- 435 [MH]+thiadiazol-2-ylbenzenesulfonamide 1054-(biphenyl-2-yloxy)-3-cyano-N-1,3-thiazol-5- 434 [MH]+ylbenzenesulfonamide 106 4-(biphenyl-2-yloxy)-3-cyano-N-pyrimidin-4- 429[MH]+ ylbenzenesulfonamide 1074-(biphenyl-2-yloxy)-3-cyano-N-(5-cyano-1,3- 457 [MH]−thiazol-2-yl)benzenesulfonamide 1084-(biphenyl-2-yloxy)-3-cyano-N-isoxazol-4- 435 [MNH₄]+ylbenzenesulfonamide 109 4-(biphenyl-2-yloxy)-3-cyano-N-1,2,5- 433 [MH]−thiadiazol-3-ylbenzenesulfonamide 1104-(biphenyl-2-yloxy)-3-cyano-N-isoxazol-3- 418 [MH]+ylbenzenesulfonamide 111 REFERENCE EXAMPLE 512 [MNH₄]+4-(biphenyl-2-yloxy)-3-cyano-N-[2-(trifluoromethyl)phenyl]benzenesulfonamide 1124-(biphenyl-2-yloxy)-3-cyano-N-(5-methyl- 449 [MH]+1,2,3-thiadiazol-4-yl)benzenesulfonamide 1134-(biphenyl-2-yloxy)-3-cyano-N-(1-methyl- 431 [MH]+1H-imidazol-2-yl)benzenesulfonamide 114 REFERENCE EXAMPLE 444 [MNH₄]+4-(biphenyl-2-yloxy)-3-cyano-N- phenylbenzenesulfonamide 1154-(biphenyl-2-yloxy)-3-cyano-N-[6- 497 [MH]+(trifluoromethyl)pyrimidin-4- yl]benzenesulfonamide 1164-(biphenyl-2-yloxy)-3-cyano-N-[2- 497 [MH]+(trifluoromethyl)pyrimidin-4- yl]benzenesulfonamide 1174-(biphenyl-2-yloxy)-3-cyano-N-1H-imidazol- 417 [MH]+2-ylbenzenesulfonamide 118 3-fluoro-N-1,3-thiazol-2-yl-4-{4-[(1,3,5- 473[MH]+ trimethyl-1H-pyrazol-4- yl)methyl]phenoxy}benzenesulfonamide 1194-[3-(benzyloxy)phenoxy]-3-fluoro-N-1,3- 457 [MH]+thiazol-2-ylbenzenesulfonamide 1204-[4-(benzyloxy)-3-fluorophenoxy]-3-fluoro- 475 [MH]+N-1,3-thiazol-2-ylbenzenesulfonamide 1213-fluoro-4-[4-(1,3-oxazol-4-yl)phenoxy]-N- 418 [MH]+1,3-thiazol-2-ylbenzenesulfonamide 122 4-{4-[(3,5-dimethylisoxazol-4-460 [MH]+ yl)methyl]phenoxy}-3-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide 123 4-[2,6-dimethyl-4-(pyrrolidin-1- 462 [MH]+ylmethyl)phenoxy]-3-fluoro-N-1,3-thiazol-2- ylbenzenesulfonamide 1243-fluoro-4-[4-(4-fluorophenoxy)phenoxy]-N- 461 [MH]+1,3-thiazol-2-ylbenzenesulfonamide 1254-[4-(azetidin-1-ylmethyl)-3-fluorophenoxy]- 438 [MH]+3-fluoro-N-1,3-thiazol-2- ylbenzenesulfonamide 1263-fluoro-4-(3-phenoxyphenoxy)-N-1,3-thiazol- 443 [MH]+2-ylbenzenesulfonamide 127 3-fluoro-4-(4-phenoxyphenoxy)-N-1,3-thiazol-443 [MH]+ 2-ylbenzenesulfonamide 1283-fluoro-4-[2-(3-methylisothiazol-5- 448 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 1293-fluoro-4-[2-(4-methylisothiazol-5- 448 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 1303-fluoro-4-[2-(2-methyl-1,3-thiazol-4- 448 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 1313-fluoro-4-(2-pyridin-2-ylphenoxy)-N-1,3- 428 [MH]+thiazol-2-ylbenzenesulfonamide 1324-[4-(3-ethyl-5-methyl-4H-1,2,4-triazol-4- 460 [MH]+yl)phenoxy]-3-fluoro-N-1,3-thiazol-2- ylbenzenesulfonamide 1333-fluoro-4-[2-(tetrahydro-2H-pyran-2- 435 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 135N-(5-chloro-1,3-thiazol-2-yl)-3-cyano-4-[2- 485 [M³⁵ClH]+ (pyridin-4-487 [M³⁷C)H]+ yloxy)phenoxy]benzenesulfonamide 1364-[2-(benzyloxy)phenoxy]-N-(5-chloro-1,3- 498 [M³⁵ClH]+thiazol-2-yl)-3-cyanobenzenesulfonamide 500 [M³⁷ClH]+ 1374-{[4-(4-chlorophenyl)-1-methyl-1H-pyrazol- 506 [M³⁵ClH]+3-yl]oxy}-N-(5-chloro-1,3-thiazol-2-yl)-3- 508 [M³⁷ClH]+cyanobenzenesulfonamide 138 N-(5-chloro-1,3-thiazol-2-yl)-3-cyano-4-[(1-472 [M³⁵ClH]+ methyl-4-phenyl-1H-pyrazol-5- 474 [M³⁷ClH]+yl)oxy]benzenesulfonamide 1394-[(1-benzyl-4-methyl-1H-pyrazol-3-yl)oxy]- 486 [M³⁵ClH]+N-(5-chloro-1,3-thiazol-2-yl)-3- 488 [M³⁷ClH]+ cyanobenzenesulfonamide140 4-{[1-(2-chlorophenyl)-3-isopropyl-1H- NMR Data was:pyrazol-4-yl]oxy}-N-(5-chloro-1,3-thiazol-2- ¹HNMR (d₆-yl)-3-cyanobenzenesulfonamide DMSO): δ 1.20 (d, 6H), 2.83-2.96 (m, 1H),7.23 (d, 1H), 7.47-7.56 (m, 2H), 7.58 (s, 1H), 7.64-7.71 (m, 2H), 8.09(dd, 1H), 8.27 (d, 1H), 8.39 (s, 1H). 141N-(5-chloro-1,3-thiazol-2-yl)-3-cyano-4-{[1- 526 [M³⁵ClH]+phenyl-3-(trifluoromethyl)-1H-pyrazol-5- 528 [M³⁷ClH]+yl]oxy}benzenesulfonamide 1424-{[1-benzyl-3-(trifluoromethyl)-1H-pyrazol- 540 [M³⁵ClH]+5-yl]oxy}-N-(5-chloro-1,3-thiazol-2-yl)-3- 542 [M³⁷ClH]+cyanobenzenesulfonamide 143 N-(5-chloro-1,3-thiazol-2-yl)-3-cyano-4-[(1-478 [M³⁵ClH]+ cyclohexyl-3-methyl-1H-pyrazol-5- 480 [M³⁷ClH]+yl)oxy]benzenesulfonamide 144N-(5-chloro-1,3-thiazol-2-yl)-3-cyano-4-(2- 432 [M³⁵ClH]+cyclopropylphenoxy)benzenesulfonamide 434 [M³⁷ClH]+ 145N-(5-chloro-1,3-thiazol-2-yl)-3-cyano-4-{[3- NMR Data was:isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4- ¹HNMR (d₆-yl]oxy}benzenesulfonamide DMSO): δ 1.2 (d, 6H), 2.85 (m, 1H), 3.8 (s,3H), 7.0 (m, 2H), 7.25 (m, 1H), 7.6 (m, 1H), 7.75 (m, 2H), 8.0 (m, 1H),8.25 (m, 1H), 8.6 (s, 1H). 1464-(biphenyl-2-yloxy)-N-(5-chloro-1,3-thiazol- 468 [MH]+2-yl)-3-cyanobenzenesulfonamide 1474-(Biphenyl-2-yloxy)-N-(5-chloro-thiazol-2- 461 [M³⁵ClH]+yl)-3-fluoro-benzenesulfonamide 1483-chloro-4-[4-(cyclopropylmethyl)phenoxy]- 422 [M³⁵ClH]+N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 1494-(biphenyl-4-yloxy)-3-chloro-N-1,2,4- 444 [M³⁵ClH]+thiadiazol-5-ylbenzenesulfonamide 446 [M³⁷ClH]+ 1504-(biphenyl-2-yloxy)-3-chloro-N-1,2,4- 444 [M³⁵ClH]+thiadiazol-5-ylbenzenesulfonamide 446 [M³⁷ClH]+ 1513-cyano-4-[4-fluoro-2-(6-methoxypyridin-3- 483 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 1523-cyano-4-[(4′,5-difluorobiphenyl-2-yl)oxy]- 470 [MH]+N-1,3-thiazol-2-ylbenzenesulfonamide 153 3-cyano-4-{[5-fluoro-3′-(2- 496[MH]+ hydroxyethyl)biphenyl-2-yl]oxy}-N-1,3-thiazol-2-ylbenzenesulfonamide 1543-cyano-4-[(5-fluoro-3′-methoxybiphenyl-2- 482 [MH]+yl)oxy]-N-1,3-thiazol-2-ylbenzenesulfonamide 1554-[(5-chloro-4′-isopropoxybiphenyl-2-yl)oxy]- 526 [M³⁵ClH]+3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 1564-[(5-chlorobiphenyl-2-yl)oxy]-3-cyano-N- 468 [M³⁵ClH]+1,3-thiazol-2-ylbenzenesulfonamide 1573-cyano-4-[(5-fluoro-4′-isopropoxybiphenyl-2- 510 [MH]+yl)oxy]-N-1,3-thiazol-2-ylbenzenesulfonamide 1583-cyano-N-1,3-thiazol-2-yl-4-[(3′,4′,5- 488 [MH]+ trifluorobiphenyl-2-yl)oxy]benzenesulfonamide 159 4-[4-chloro-2-(2-methyl-1H-imidazol-1- 472[M³⁵ClH]+ yl)phenoxy]-3-cyano-N-1,3-thiazol-2- 474 [M³⁷ClH]+ylbenzenesulfonamide 160 3-cyano-4-{[5-fluoro-3′- 496 [MH]+(methoxymethyl)biphenyl-2-yl]oxy}-N-1,3- thiazol-2-ylbenzenesulfonamide161 3-cyano-4-{[5-fluoro-3′- 482 [MH]+(hydroxymethyl)biphenyl-2-yl]oxy}-N-1,3- thiazol-2-ylbenzenesulfonamide162 3-cyano-4-{[5-fluoro-4′- 482 [MH]+(hydroxymethyl)biphenyl-2-yl]oxy}-N-1,3- thiazol-2-ylbenzenesulfonamide163 3-cyano-4-{[5-fluoro-4′- 496 [MH]+(methoxymethyl)biphenyl-2-yl]oxy}-N-1,3- thiazol-2-ylbenzenesulfonamide164 4-(4-chloro-2-pyridin-2-ylphenoxy)-3-cyano- 470 [M³⁵ClH]+N-1,3-thiazol-2-ylbenzenesulfonamide 1654-(biphenyl-2-yloxy)-3-cyano-N-(thiazol-2- 434 [MH]+yl)benzenesulfonamide 166 3-cyano-4-(2-(2-methylthiazol-4-yl)phenoxy)-455 [MH]+ N-(thiazol-2-yl)benzenesulfonamide 1674-(1-(4-chlorobenzyl)-1H-pyrazol-4-yloxy)-3- 472 [M³⁵ClH]+cyano-N-(thiazol-2-yl)benzenesulfonamide 1683-cyano-4-(1-phenyl-3-(trifluoromethyl)-1H- 492 [MH]+pyrazol-5-yloxy)-N-(thiazol-2- yl)benzenesulfonamide 1693-cyano-4-(4-fluoro-2-(1-methyl-1H-pyrazol- 456 [MH]+5-yl)phenoxy)-N-(thiazol-2- yl)benzenesulfonamide 1704-(4-chloro-2-(1-methyl-1H-pyrazol-5- 472 [M³⁵ClH]+yl)phenoxy)-3-cyano-N-(thiazol-2- yl)benzenesulfonamide 1714-(4-chloro-2-(1-phenyl-1H-pyrazol-5- 534 [M³⁵ClH]+yl)phenoxy)-3-cyano-N-(thiazol-2- yl)benzenesulfonamide 1723-cyano-4-(2-(1-methyl-1H-pyrazol-5- 438 [MH]+ yl)phenoxy)-N-(thiazol-2-yl)benzenesulfonamide 173 4-(2-(1,3,4-oxadiazol-2-yl)phenoxy)-3-cyano-426 [MH]+ N-(thiazol-2-yl)benzenesulfonamide 1743-cyano-4-(2-(isoxazol-5-yl)phenoxy)-N- 425 [MH]+(thiazol-2-yl)benzenesulfonamide 175 3-cyano-4-(4-fluoro-2-(1-(2,2,2-524 [MH]+ trifluoroethyl)-1H-pyrazol-5-yl)phenoxy)-N-(thiazol-2-yl)benzenesulfonamide 1763-cyano-4-(4-fluoro-2-(5-methyl-1H-pyrazol- 456 [MH]+1-yl)phenoxy)-N-(thiazol-2- yl)benzenesulfonamide 1774-(4-chloro-2-(1-(2,2,2-trifluoroethyl)-1H- 540 [M³⁵ClH]+pyrazol-5-yl)phenoxy)-3-cyano-N-(thiazol-2- yl)benzenesulfonamide 1784-(2-chloro-4-(1-methyl-1H-pyrazol-3- 472 [M³⁵ClH]+yl)phenoxy)-3-cyano-N-(thiazol-2- yl)benzenesulfonamide 1794-(2-chloro-4-(1-methyl-1H-pyrazol-5- 472 [M³⁵ClH]+yl)phenoxy)-3-cyano-N-(thiazol-2- yl)benzenesulfonamide 1803-cyano-4-(2-(1-ethyl-1H-pyrazol-5-yl)-4- 471 [MH]+fluorophenoxy)-N-(thiazol-2- yl)benzenesulfonamide 1813-cyano-4-(2-(4-phenyl-4H-1,2,4-triazol-3- 501 [MH]+yl)phenoxy)-N-(thiazol-2- yl)benzenesulfonamide 1824-(4-chloro-2-(4-methyl-4H-1,2,4-triazol-3- 473 [M³⁵ClH]+yl)phenoxy)-3-cyano-N-(thiazol-2- yl)benzenesulfonamide 1833-cyano-N-thiazol-2-yl-4-[4-(3- 492 [MH]+trifluoromethyl-pyrazol-1-yl)-phenoxy]- benzenesulfonamide 1844-[4-(1-tert-butyl-1H-pyrazol-3-yl)-2-fluoro- 498 [MH]+phenoxy]-3-cyano-N-thiazol-2-yl- benzenesulfonamide 1853-cyano-4-[2-fluoro-4-(1H-pyrazol-3-yl)- 442 [MH]+phenoxy]-N-thiazol-2-yl-benzenesulfonamide 1863-cyano-4-[4-(3,5-dimethyl-pyrazol-1-yl)- 452 [MH]+phenoxy]-N-thiazol-2-yl-benzenesulfonamide 1874-(biphenyl-4-yloxy)-3-cyano-N-thiazol-2-yl- 434 [MH]+benzenesulfonamide 188 3-cyano-4-[5-(2-fluoro-phenyl)-2-(2,2,2- 524[MH]+ trifluoro-ethyl)-2H-pyrazol-3-yloxy]-N-thiazol-2-yl-benzenesulfonamide 1894-[5-(4-chloro-phenyl)-2-(2,2,2-trifluoro- 540 [M³⁵ClH]+ethyl)-2H-pyrazol-3-yloxy]-3-cyano-N- thiazol-2-yl-benzenesulfonamide190 3-cyano-4-[5-phenyl-2-(2,2,2-trifluoro-ethyl)- 506 [MH]+2H-pyrazol-3-yloxy]-N-thiazol-2-yl- benzenesulfonamide 1913-cyano-4-(5-cyclopropyl-2-pyridin-2-yl-2H- 465 [MH]+pyrazol-3-yloxy)-N-thiazol-2-yl- benzenesulfonamide 1923-Cyano-4-(2-cyclohexyl-5-cyclopropyl-2H- 470 [MH]+pyrazol-3-yloxy)-N-thiazol-2-yl- benzenesulfonamide 1933-cyano-4-[5-cyclopropyl-2-(2-fluoro-phenyl)- 482 [MH]+2H-pyrazol-3-yloxy]-N-thiazol-2-yl- benzenesulfonamide 1943-Cyano-4-[5-cyclopropyl-2-(2,2,2-trifluoro- 470 [MH]+ethyl)-2H-pyrazol-3-yloxy]-N-thiazol-2-yl- benzenesulfonamide 1953-Cyano-4-[5-cyclopropyl-2-(2,5-difluoro- 500 [MH]+phenyl)-2H-pyrazol-3-yloxy]-N-thiazol-2-yl- benzenesulfonamide 1964-[4-Chloro-2-(4-fluoro-2-methyl-2H-pyrazol- 490 [M³⁵ClH]+3-yl)-phenoxy]-3-cyano-N-thiazol-2-yl- benzenesulfonamide 1974-(4-chloro-3-methyl-2-[1,3,4]oxadiazol-2-yl- 474 [M³⁵ClH]+phenoxy)-3-cyano-N-thiazol-2-yl- benzenesulfonamide 1984-[2-(2-tert-butyl-2H-pyrazol-3-yl)-3-chloro- 514 [M³⁵ClH]+phenoxy]-3-cyano-N-thiazol-2-yl- benzenesulfonamide 1994-[3-chloro-2-(2H-pyrazol-3-yl)-phenoxy]-3- 458 [M³⁵ClH]+cyano-N-thiazol-2-yl-benzenesulfonamide 2003-cyano-4-(2-(3-methyl-1H-pyrazol-4- 438 [MH]+ yl)phenoxy)-N-(thiazol-2-yl)benzenesulfonamide 201 3-cyano-4-{[5-fluoro-4′-(2- 496 [MH]+hydroxyethyl)biphenyl-2-yl]oxy}-N-1,3- thiazol-2-ylbenzenesulfonamide202 3-cyano-N-thiazol-2-yl-4-[4-(5- 492 [MH]+trifluoromethyl-2H-pyrazol-3-yl)-phenoxy]- benzenesulfonamide 2035-(N-thiazol-2-ylsulfamoyl)-2-(4-(3- 510 [MH]+(trifluoromethyl)-1H-pyrazol-5- yl)phenoxy)benzamide 2044-{[1-(4-chlorobenzyl)-1H-pyrazol-3-yl]oxy}- NMR Data was:N-1,2,4-thiadiazol-5-yl-3- ¹HNMR (d₆-(trifluoromethyl)benzenesulfonamide DMSO): δ 5.2 (s, 2H), 6.1 (m, 1H),7.25 (m, 3H), 7.4 (m, 2H), 7.9 (m, 1H), 8.0 (m, 2H), 8.45 (s, 1H). 2054-(biphenyl-2-yloxy)-N-1,2,4-thiadiazol-5-yl- NMR Data was:3-(trifluoromethyl)benzenesulfonamide ¹HNMR (d₆- DMSO): δ 6.86 (d, 1H, J= 8.4 Hz), 7.23-7.49 (m, 8H), 7.58 (d, 1H, J = 7.6 Hz), 7.89-7.92 (m,2H), 8.39 (s, 1H). 206 4-(1-(4-chlorobenzyl)-1H-pyrazol-4-yloxy)-2- 465[M³⁵ClH]+ fluoro-N-(thiazol-2-yl)benzenesulfonamide 2072-fluoro-4-(2′-methoxybiphenyl-2-yloxy)-N- 457 [MH]+(thiazol-2-yl)benzenesulfonamide 2082-fluoro-4-(2′-methoxybiphenyl-2-yloxy)-N- 427 [MH]+(thiazol-2-yl)benzenesulfonamide 2094-(biphenyl-4-yloxy)-2-fluoro-N-(thiazol-2- 427 [MH]+yl)benzenesulfonamide 210 4-(biphenyl-3-yloxy)-2-fluoro-N-(thiazol-2-427 [MH]+ yl)benzenesulfonamide 2114-(4-chloro-2-(1-phenyl-1H-pyrazol-5- 527 [M³⁵ClH]+yl)phenoxy)-2-fluoro-N-(thiazol-2- yl)benzenesulfonamide 2124-(2-(1-tert-butyl-1H-pyrazol-3-yl)-4- 491 [MH]+fluorophenoxy)-2-fluoro-N-(thiazol-2- yl)benzenesulfonamide 2132-fluoro-4-(4-fluoro-2-(1H-pyrazol-5- 435 [MH]+yl)phenoxy)-N-(thiazol-2- yl)benzenesulfonamide 2144-[4-(4-chloro-benzyl)-thiazol-2-yloxy]-2- 482 [M³⁵ClH]+fluoro-N-thiazol-2-yl-benzenesulfonamide 2153-fluoro-4-(4-methyl-2-(1-methyl-1H-pyrazol- 431 [MH]+3-yl)phenoxy)-N-(thiazol-2- yl)benzenesulfonamide 2164-(4-chloro-2-(1-methyl-1H-pyrazol-3- 465 [M³⁵ClH]+yl)phenoxy)-3-fluoro-N-(thiazol-2- yl)benzenesulfonamide 2174-(2-(1-tert-butyl-1H-pyrazol-5-yl)-4- 491 [MH]+fluorophenoxy)-3-fluoro-N-(thiazol-2- yl)benzenesulfonamide 2183-fluoro-4-(4-fluoro-2-(1H-pyrazol-5- 435 [MH]+yl)phenoxy)-N-(thiazol-2- yl)benzenesulfonamide 2194-(4-chloro-2-(1-methyl-1H-pyrazol-5- 465 [M³⁵ClH]+yl)phenoxy)-3-fluoro-N-(thiazol-2- yl)benzenesulfonamide 2204-(2-(1-benzyl-1H-pyrazol-5-yl)-4- 541 [M³⁵ClH]+chlorophenoxy)-3-fluoro-N-(thiazol-2- yl)benzenesulfonamide 221 ethyl2-(5-(5-fluoro-2-(2-fluoro-4-(N-thiazol- 521 [MH]+2-ylsulfamoyl)phenoxy)phenyl)-1H-pyrazol-1- yl)acetate 2223-fluoro-4-(4-methyl-2-(1-methyl-1H-pyrazol- 445 [MH]+5-yl)phenoxy)-N-(thiazol-2- yl)benzenesulfonamide 2234-(2-(1-tert-butyl-4-methyl-1H-pyrazol-5-yl)- 501 [MH]+4-methylphenoxy)-3-fluoro-N-(thiazol-2- yl)benzenesulfonamide 2243-fluoro-4-(4-methyl-2-(4-methyl-1H-pyrazol- 445 [MH]+5-yl)phenoxy)-N-(thiazol-2- yl)benzenesulfonamide 2253-fluoro-4-(4-fluoro-2-(1-(2,2,2- 517 [MH]+trifluoroethyl)-1H-pyrazol-5-yl)phenoxy)-N-(thiazol-2-yl)benzenesulfonamide 2264-(4-bromo-2-(1-methyl-1H-pyrazol-5- 511 [M⁸¹BrH]+yl)phenoxy)-3-fluoro-N-(thiazol-2- yl)benzenesulfonamide 2274-(4-chloro-2-(1-phenyl-1H-pyrazol-5- 527 [M³⁵ClH]+yl)phenoxy)-3-fluoro-N-(thiazol-2- yl)benzenesulfonamide 2284-[2-(2,5-difluoro-phenyl)-5-trifluoromethyl- 521 [MH]+2H-pyrazol-3-yloxy]-3-fluoro-N-thiazol-2-yl- benzenesulfonamide 2293-fluoro-4-(2-phenyl-5-trifluoromethyl-2H- 485 [MH]+pyrazol-3-yloxy)-N-thiazol-2-yl- benzenesulfonamide 2303-fluoro-4-[2-(2-fluoro-phenyl)-5- 503 [MH]+trifluoromethyl-2H-pyrazol-3-yloxy]-N- thiazol-2-yl-benzenesulfonamide231 3-fluoro-4-(5-methyl-2-phenyl-2H-pyrazol-3- 431 [MH]+yloxy)-N-thiazol-2-yl-benzenesulfonamide 2324-[1-(4-chloro-benzyl)-1H-pyrazol-3-yloxy]-3- 465 [M³⁵ClH]+fluoro-N-thiazol-2-yl-benzenesulfonamide 2333-fluoro-4-(1-methyl-4-phenyl-1H-pyrazol-3- 431 [MH]+yloxy)-N-(thiazol-2-yl)benzenesulfonamide 2343-fluoro-4-(4-(methoxymethyl)-2-(1-methyl- 475 [MH]+1H-pyrazol-5-yl)phenoxy)-N-(thiazol-2- yl)benzenesulfonamide 2354-(1-(4-chlorobenzyl)-1H-pyrazol-4-yloxy)-3- 465 [M³⁵ClH]+fluoro-N-(thiazol-2-yl)benzenesulfonamide 2363-fluoro-4-(5-phenylpyrimidin-4-yloxy)-N- 429 [MH]+(thiazol-2-yl)benzenesulfonamide 2373-fluoro-4-{4-fluoro-2-[1-(2-hydroxyethyl)- 479 [MH]+1H-pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 2382-(5-(5-fluoro-2-(2-fluoro-4-(N-thiazol-2- 493 [MH]+ylsulfamoyl)phenoxy)phenyl)-1H-pyrazol-1- yl)acetic acid 2392-(5-(5-fluoro-2-(2-fluoro-4-(N-thiazol-2- 520 [MH]+ylsulfamoyl)phenoxy)phenyl)-1H-pyrazol-1- yl)-N,N-dimethylacetamide 2404-[2-tert-butyl-5-(4-chloro-benzyl)-2H- 521 [M³⁵ClH]+pyrazol-3-yloxy]-3-fluoro-N-thiazol-2-yl- benzenesulfonamide 2414-[5-(4-chloro-benzyl)-2-methyl-2H-pyrazol- 479 [M³⁵ClH]+3-yloxy]-3-fluoro-N-thiazol-2-yl- benzenesulfonamide 2424-(biphenyl-2-yloxy)-3-fluoro-N-thiazol-2-yl- 427 [MH]+benzenesulfonamide 243 4-(3-(4-chlorobenzyl)-1H-pyrazol-5-yloxy)-3- 465[MH]+ fluoro-N-(thiazol-2-yl)benzenesulfonamide 2444-(4-chloro-3-methyl-2-[1,3,4]oxadiazol-2-yl- 467 [M³⁵ClH]+phenoxy)-3-fluoro-N-thiazol-2-yl- benzenesulfonamide 2454-[4-(2-tert-butyl-5-trifluoromethyl-2H- 541 [MH]+pyrazol-3-yl)-phenoxy]-3-fluoro-N-thiazol-2- yl-benzenesulfonamide 2463-fluoro-N-(thiazol-2-yl)-4-(4-(3- 485 [MH]+(trifluoromethyl)-1H-pyrazol-5- yl)phenoxy)benzenesulfonamide 2474-(biphenyl-4-yloxy)-3-fluoro-N-thiazol-2-yl- 427 [MH]+benzenesulfonamide 248 4-[4-(3,5-dimethyl-pyrazol-1-yl)-phenoxy]-3- 445[MH]+ fluoro-N-thiazol-2-yl-benzenesulfonamide 2492-(1-(4-chlorobenzyl)-1H-pyrazol-4-yloxy)-5- 490 [M³⁵ClH]+(N-thiazol-2-ylsulfamoyl)benzamide 2502-(biphenyl-2-yloxy)-5-(N-thiazol-2- 452 [MH]+ ylsulfamoyl)benzamide 2514-(biphenyl-2-yloxy)-3-fluoro-N-(1,3,4- 428 [MH]+thiadiazol-2-yl)benzenesulfonamide 2524-(2-(1-benzyl-3-methyl-1H-pyrazol-4- 522 [MH]+yl)phenoxy)-3-fluoro-N-(1,2,4-thiadiazol-5- yl)benzenesulfonamide 2534-[2-(2,5-difluoro-phenyl)-5-trifluoromethyl- 522 [MH]+2H-pyrazol-3-yloxy]-3-fluoro-N-1,2,4- thiadiazol-5-yl-benzenesulfonamide254 3-fluoro-4-(2-phenyl-5-trifluoromethyl-2H- 486 [MH]+pyrazol-3-yloxy)-N-1,2,4-thiadiazol-5-yl- benzenesulfonamide 2553-fluoro-4-[2-(2-fluoro-phenyl)-5- 504 [MH]+trifluoromethyl-2H-pyrazol-3-yloxy]-N-1,2,4-thiadiazol-5-yl-benzenesulfonamide 2564-(biphenyl-2-yloxy)-3-methyl-N-1,2,4- NMR Data was:thiadiazol-5-ylbenzenesulfonamide ¹HNMR (d₆- DMSO): δ 2.24 (s, 3H), 6.65(m, 1H), 7.09 (m, 1H), 7.25-7.53 (m, 9H), 7.62 (m, 1H), 8.44 (s, 1H).257 4-{[1-(4-chlorobenzyl)-1H-pyrazol-3-yl]oxy}- NMR Data was:3-methyl-N-1,2,4-thiadiazol-5- ¹H NMR (400 ylbenzenesulfonamide MHz, d₆-DMSO): δ 2.3 (s, 3H), 5.22 (s, 2H), 5.9 (m, 1H), 7.0 (m, 1H), 7.2 (m,2H), 7.4 (m, 2H), 7.6 (m, 1H), 7.8 (m, 1H), 8.45 (s, 1H). 2584-(biphenyl-2-yloxy)-3-methyl-N-1,3-thiazol- 423 [MH]+2-ylbenzenesulfonamide 259 4-{[1-(4-chlorobenzyl)-1H-pyrazol-3-yl]oxy}-NMR Data was: 3-methoxy-N-1,2,4-thiadiazol-5- ¹HNMR (d₆-ylbenzenesulfonamide DMSO): δ 3.8 (s, 3H), 5.2 (s, 2H), 5.9 (m, 1H), 7.1(m, 1H), 7.2 (m, 2H), 7.4 (m, 3H), 7.8 (m, 1H), 8.45 (s, 1H) 2604-(biphenyl-2-yloxy)-N-1,2,4-thiadiazol-5-yl- NMR Data was:2-(trifluoromethyl)benzenesulfonamide ¹HNMR (d₆- DMSO): δ 7.15 (m, 1H),7.25-7.36 (m, 5H), 7.42-7.44 (m, 3H), 7.49 (m, 1H), 7.56 (m, 1H), 8.05(m, 1H), 8.46 (s, 1H) 261 4-(biphenyl-2-yloxy)-2-methyl-N-1,2,4- NMRData was: thiadiazol-5-ylbenzenesulfonamide ¹HNMR (d₆- DMSO): δ 2.4 (s,3H), 6.7 (m, 1H), 6.9 (m, 1H), 7.1 (m, 1H), 7.2-7.5 (m, 8H), 7.8 (m,1H), 8.4 (s, 1H) 262 4-(biphenyl-2-yloxy)-3-methoxy-N-1,2,4- NMR Datawas: thiadiazol-5-ylbenzenesulfonamide ¹HNMR (d₆- DMSO): δ 3.8 (s, 3H),6.9 (m, 2H), 7.2-7.4 (m, 7H), 7.45-7.5 (m, 3H), 8.44 (s, 1H) 2634-(biphenyl-2-yloxy)-2-chloro-N-1,2,4- NMR Data was:thiadiazol-5-ylbenzenesulfonamide ¹HNMR (d₆- DMSO): δ 6.89 (dd, 1H, J =2.4 & 8.8 Hz), 7.07 (d, 1H, J = 2.4 Hz), 7.24-7.50 (m, 8H), 7.55 (dd,1H, J = 2.0 & 7.6 Hz), 7.94 (d, 1H, J = 8.8 Hz), 8.48 (s, 1H) 2644-(biphenyl-2-yloxy)-3,5-difluoro-N-1,2,4- NMR Data was:thiadiazol-5-ylbenzenesulfonamide ¹HNMR (d₆- DMSO): δ 6.90 (m, 1H),7.16- 7.70 (m, 10H), 8.48 (s, 1H) 2654-{[1-(4-chlorobenzyl)-1H-pyrazol-3-yl]oxy}- NMR Data was:3,5-difluoro-N-1,2,4-thiadiazol-5- ¹HNMR (d₆- ylbenzenesulfonamideDMSO): δ 5.15 (s, 2H), 5.97 (d, 1H, J = 2.0 Hz), 7.15 (d, 2H, J = 8.0Hz), 7.39 (d, 2H, J = 8.0 Hz), 7.67 (d, 2H, J = 6.8 Hz), 7.76 (d, 1H, J= 2.0 Hz), 8.46 (s, 1H) 266 4-(biphenyl-2-yloxy)-2,5-difluoro-N-1,2,4-NMR Data was: thiadiazol-5-ylbenzenesulfonamide ¹HNMR (d₆- DMSO): δ6.89-6.90 (m, 1H), 7.22 (m, 1H), 7.29-7.53 (m, 8H), 7.68- 7.70 (m, 1H),8.47 (s, 1H) 267 4-(biphenyl-2-yloxy)-2-chloro-5-fluoro-N- NMR Data was:1,2,4-thiadiazol-5-ylbenzenesulfonamide ¹HNMR (d₆- DMSO): δ 7.01 (m,1H), 7.24 (m, 1H), 7.28-7.48 (m, 7H), 7.53 (m, 1H), 7.88 (d, 1H) 8.49(s, 1H) 268 4-(biphenyl-2-yloxy)-2-cyano-N-1,2,4- 435 [MH]+thiadiazol-5-ylbenzenesulfonamide 2694-(biphenyl-2-yloxy)-2,3-difluoro-N-1,2,4- NMR Data was:thiadiazol-5-ylbenzenesulfonamide ¹HNMR (d₆- DMSO): δ 6.70-6.74 (m, 1H),7.26-7.55 (m, 10H), 8.43 (s, 1H) 2704-(biphenyl-2-yloxy)-5-chloro-2-fluoro-N- NMR Data was:1,2,4-thiadiazol-5-ylbenzenesulfonamide ¹HNMR (d₆- DMSO): δ 6.72 (m,1H), 7.22 (m, 1H), 7.27 (m, 1H), 7.36 (m, 2H), 7.39-7.48 (m, 4H), 7.54(m, 1H), 7.79 (m, 1H), 8.41 (s, 1H) 2714-(biphenyl-2-yloxy)-3-fluoro-N-thiazol-4-yl- 427 [MH]+benzenesulfonamide 272 4-[4-chloro-2-(2-methyl-2H-pyrazol-3-yl)- 465[M³⁵ClH]+ phenoxy]-3-fluoro-N-thiazol-4-yl- benzenesulfonamide 2734-(biphenyl-4-yloxy)-3-fluoro-N-thiazol-4-yl- 427 [MH]+benzenesulfonamide 274 3-fluoro-4-(2-phenyl-5-trifluoromethyl-2H- 485[MH]+ pyrazol-3-yloxy)-N-thiazol-4-yl- benzenesulfonamide 2754-[4-chloro-2-(2-methyl-2H-pyrazol-3-yl)- 483 [M³⁵ClH]+phenoxy]-3-fluoro-N-(5-fluoro-thiazol-2-yl)- benzenesulfonamide 2764-(biphenyl-2-yloxy)-N-thiazol-2-yl- 409 [MH]+ benzenesulfonamide 2774-(5-methyl-2-phenyl-2H-pyrazol-3-yloxy)-N- 413 [MH]+thiazol-2-yl-benzenesulfonamide 2786-(biphenyl-2-yloxy)-pyridine-3-sulfonic acid 410 [MH]+thiazol-2-ylamide 280 3-cyano-4-[4-(2-ethyl-5-trifluoromethyl-2H- 520[MH]+ pyrazol-3-yl)-phenoxy]-N-thiazol-2-yl- benzenesulfonamide 2814-(4-(1-tert-butyl-3-(trifluoromethyl)-1H- 566 [MH]+pyrazol-5-yl)phenoxy)-3-cyano-N-(5-fluorothiazol-2-yl)benzenesulfonamide 2823-cyano-4-[4-(2-methyl-5-trifluoromethyl-2H- 506 [MH]+pyrazol-3-yl)-phenoxy]-N-thiazol-2-yl- benzenesulfonamide

The following further examples can be prepared analogously to theGeneral Schemes described above, Library Protocols 1 and 2 (as describedabove and below) and Methods A-M as described for Examples 1-6, 95-99,134, 170, and 279 above, or any of the other fully written upexperimental conditions provided, substituting appropriate startingmaterials where necessary and making appropriate changes to experimentalconditions informed by the schemes and conditions provided and commongeneral knowledge. Purification was performed either by silica gelcolumn chromatography, trituration or preparative HPLC.

Library Protocol 2

To the phenol (60 μmol) was added 600 μL of a prepared dimethylsulphoxide solution of3-cyano-4-fluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide (Preparation301, 40 μmol per 600 μL). Potassium carbonate (16.6 mg, 120 μmol) wasadded and the mixture was stirred at 90° C. for 60 hours. The reactionmixture was cooled to room temperature and filtered. The filtrate waspurified by preparative HPLC to afford the title compound.

MS m/z Eg (unless otherwise No Name incidated) 2834-[4-chloro-2-(1-isopropyl-1H-pyrazol-4- 501 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 2843-cyano-4-[2-(5-cyanopyridin-3-yl)-4- 529 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 2854-[2-(1-tert-butyl-1H-pyrazol-5-yl)-4- 499 [MH]+fluorophenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 2864-[4-chloro-2-(1-methyl-1H-pyrazol-3- 473 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 287[1-(4-{2-cyano-4-[(1,2,4-thiadiazol-5- 551 [MH]+ylamino)sulfonyl]phenoxy}phenyl)-1H-pyrazol- 4-yl]methyltrifluoroacetate 288 3-cyano-4-{4-[4-(hydroxymethyl)-1H-pyrazol-1- 455[MH]+ yl]phenoxy}-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 2893-cyano-4-[4-iodo-2-(1H-pyrazol-4-yl)phenoxy]- 551 [MH]⁺N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 2903-cyano-4-{3-[1-ethyl-3-(trifluoromethyl)-1H- 535 [MH]+pyrazol-5-yl]phenoxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzenesulfonamide 2913-cyano-4-{4-[1-ethyl-3-(trifluoromethyl)-1H- 535 [MH]+pyrazol-5-yl]phenoxy}-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzenesulfonamide 292 3-cyano-4-{2-cyano-4-[1-methyl-3-531 [MH]+ (trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2-ylbenzenesulfonamide 293 3-cyano-4-{2-cyano-4-[1-methyl-3-532 [MH]+ (trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 2945-chloro-4-[4-chloro-2-(1-methyl-1H-pyrazol-5- 514 [M³⁵ClH]+yl)phenoxy]-2-fluoro-N-(3-methyl-1,2,4- 516 [M³⁷ClH]+thiadiazol-5-yl)benzenesulfonamide 2955-chloro-2-fluoro-4-[4-fluoro-2-(1-methyl-1H- 478 [M³⁵ClH]+pyrazol-5-yl)phenoxy]-N-pyrimidin-4- 480 [M³⁷ClH]+ ylbenzenesulfonamide296 5-chloro-4-{2-cyano-4-[1-methyl-3- 558 [M³⁵ClH]+(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-2- 560 [M³⁷ClH]+fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide 2975-chloro-4-{2-cyano-4-[1-methyl-3- 559 [M³⁵ClH]⁺(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-2-fluoro-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 2985-chloro-2-fluoro-4-[4-fluoro-2-(1-methyl-1H- 484 [M³⁵ClH]+pyrazol-5-yl)phenoxy]-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 2995-chloro-4-[4-chloro-2-(1-methyl-1H-pyrazol-5- 500 [M³⁵ClH]+yl)phenoxy]-2-fluoro-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 3005-chloro-4-[4-chloro-2-(1H-pyrazol-5- 486 [M³⁵ClH]+yl)phenoxy]-2-fluoro-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 3014-[4-chloro-2-(1-methyl-1H-pyrazol-5- 484 [M³⁵ClH]+yl)phenoxy]-2,5-difluoro-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 3024-[4-chloro-2-(1H-pyrazol-5-yl)phenoxy]-2,5- 470 [M³⁵ClH]+difluoro-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 3034-{4-[1-tert-Butyl-3-(trifluoromethyl)-1H- 541 [MH]+pyrazol-5-yl]phenoxy}-2-fluoro-N-1,3-thiazol-2- ylbenzenesulfonamide 3045-chloro-4-[4-chloro-2-(1-methyl-1H-pyrazol-5- 499 [M³⁵ClH]+yl)phenoxy]-2-fluoro-N-1,3-thiazol-2- ylbenzenesulfonamide 3055-chloro-4-{4-[1-ethyl-3-(trifluoromethyl)-1H- 547 [M³⁵ClH]+pyrazol-5-yl]phenoxy}-2-fluoro-N-1,3-thiazol-2- ylbenzenesulfonamide 3064-[4-chloro-2-(4-methyl-4H-1,2,4-triazol-3- 466 [M³⁵ClH]+yl)phenoxy]-3-fluoro-N-1,3-thiazol-2- ylbenzenesulfonamide 3074-[4-Chloro-2-(4-fluoro-1-methyl-1H-pyrazol-5- 483 [M³⁵ClH]+yl)phenoxy]-3-fluoro-N-1,3-thiazol-2- ylbenzenesulfonamide 3084-[4-Chloro-2-(1H-pyrazol-5-yl)phenoxy]-3- 451 [M³⁵ClH]+fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide 3094-[4-Cyclopropyl-2-(1-methyl-1H-pyrazol-5- 471 [MH]+yl)phenoxy]-3-fluoro-N-1,3-thiazol-2- ylbenzenesulfonamide 3103-cyano-4-[4-fluoro-2-(3-isopropoxy-1-methyl- 514 [MH]+1H-pyrazol-5-yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 3113-cyano-N-(3,5-difluoropyridin-2-yl)-4-{4-[1- 550 [MH]+ethyl-3-(trifluoromethyl)-1H-pyrazol-5- yl]phenoxy}benzenesulfonamide312 3-cyano-4-[4-iodo-2-(1-methyl-1H-pyrazol-5- 564 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 3134-[4-chloro-2-(1-methyl-1H-pyrazol-5- 472 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-4- ylbenzenesulfonamide 3144-[4-chloro-2-(1H-pyrazol-4-yl)phenoxy]-3- 470 [M³⁵ClH]+cyano-N-(5-fluoropyridin-2- yl)benzenesulfonamide 3153-cyano-N-(5-fluoropyridin-2-yl)-4-[2-(1H- 504 [MH]+ pyrazol-4-yl)-4-(trifluoromethyl)phenoxy]benzenesulfonamide 3163-cyano-4-{4-[1-ethyl-4-(trifluoromethyl)-1H- 520 [MH]+imidazol-2-yl]phenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 3173-cyano-4-[4-(4-methyl-1,3-oxazol-2- 439 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 3184-[4-chloro-2-(4-methyl-1,3-oxazol-2- 473 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 3193-cyano-4-[3-(1H-pyrazol-1-yl)phenoxy]-N-1,3- 424 [MH]+thiazol-2-ylbenzenesulfonamide 3203-cyano-4-{4-[1-methyl-4-(trifluoromethyl)-1H- 506 [MH]+imidazol-2-yl]phenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 3214-[4-chloro-2-(2H-1,2,3-triazol-2-yl)phenoxy]-3- 459 [M³⁵ClH]⁺cyano-N-1,3-thiazol-2-ylbenzenesulfonamide 3224-[4-chloro-2-(1H-1,2,3-triazol-1-yl)phenoxy]-3- 459 [M³⁵ClH]+cyano-N-1,3-thiazol-2-ylbenzenesulfonamide 3234-{4-chloro-2-[1-(ethoxymethyl)-1H-1,2,3- 515 [M³⁵ClH]−triazol-5-yl]phenoxy}-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 3243-cyano-4-{4-[1-ethyl-5-(trifluoromethyl)-1H- 538 [MH]+pyrazol-3-yl]-2-fluorophenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 3254-[4-chloro-2-(1-methyl-1H-1,2,4-triazol-3- 473 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 3264-[4-chloro-2-(1-methyl-1H-1,2,4-triazol-5- 473 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 3273-cyano-4-{4-[1-ethyl-3-(trifluoromethyl)-1H- 538 [MH]+pyrazol-5-yl]-3-fluorophenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 3283-cyano-4-{4-[1-ethyl-3-(trifluoromethyl)-1H- 538 [MH]+pyrazol-5-yl]-2-fluorophenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 3293-cyano-4-{3-fluoro-4-[1-methyl-3- 524 [MH]+(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2-ylbenzenesulfonamide 3303-cyano-4-{2-fluoro-4-[1-methyl-3- 524 [MH]+(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2-ylbenzenesulfonamide 3314-{[1-(4-chlorobenzyl)-1H-pyrazol-4-yl]oxy}-3- 472 [M³⁵ClH]+cyano-N-1,3-thiazol-2-ylbenzenesulfonamide 3324-{[1-(4-chlorophenyl)-1H-pyrazol-4-yl]oxy}-3- 458 [M³⁵ClH]+cyano-N-1,3-thiazol-2-ylbenzenesulfonamide 3333-cyano-4-{[1-(2,4-dichlorophenyl)-1H-pyrazol- 492 [M³⁵ClH]+4-yl]oxy}-N-1,3-thiazol-2-ylbenzenesulfonamide 3343-cyano-N-1,3-thiazol-2-yl-4-({1-[3- 492 [MH]+(trifluoromethyl)phenyl]-1H-pyrazol-4- yl}oxy)benzenesulfonamide 3354-{2-chloro-4-[1-methyl-3-(trifluoromethyl)-1H- 540 [M³⁵ClH]+pyrazol-5-yl]phenoxy}-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 3364-[4-chloro-3-(1H-1,2,4-triazol-1- 473 [M³⁵ClH]+ylmethyl)phenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 3373-cyano-4-{4-[1-ethyl-3-(trifluoromethyl)-1H- 504 [MH]+pyrazol-5-yl]phenoxy}-N-isoxazol-3- ylbenzenesulfonamide 3383-cyano-4-{4-[1-ethyl-3-(trifluoromethyl)-1H- 533 [MH]+pyrazol-5-yl]phenoxy}-N-(5-fluoropyrimidin-2- yl)benzenesulfonamide 339N-(3-chloropyridin-2-yl)-3-cyano-4-{4-[1-ethyl- 548 [M³⁵ClH]+3-(trifluoromethyl)-1H-pyrazol-5- yl]phenoxy}benzenesulfonamide 3403-cyano-4-{4-[1-ethyl-3-(trifluoromethyl)-1H- 582 [MH]+pyrazol-5-yl]phenoxy}-N-[5- (trifluoromethyl)pyridin-2-yl]benzenesulfonamide 341 3-cyano-4-{4-[1-ethyl-3-(trifluoromethyl)-1H-521 [MH]+ pyrazol-5-yl]phenoxy}-N-1,2,5-thiadiazol-3-ylbenzenesulfonamide 342 3-cyano-N-(4-cyanopyridin-2-yl)-4-{4-[1-ethyl-539 [MH]+ 3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}benzenesulfonamide 3433-cyano-N-(5-cyanopyridin-2-yl)-4-{4-[1-ethyl- 539 [MH]+3-(trifluoromethyl)-1H-pyrazol-5- yl]phenoxy}benzenesulfonamide 3443-cyano-4-{4-[1-ethyl-3-(trifluoromethyl)-1H- 513 [MH]−pyrazol-5-yl]phenoxy}-N-pyrimidin-2- ylbenzenesulfonamide 3453-cyano-4-{4-[1-ethyl-3-(trifluoromethyl)-1H- 530 [MH]−pyrazol-5-yl]phenoxy}-N-(3-fluoropyridin-2- yl)benzenesulfonamide 3463-cyano-4-{4-[1-ethyl-3-(trifluoromethyl)-1H- 519 [MH]−pyrazol-5-yl]phenoxy}-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 3473-fluoro-4-[4-fluoro-2-(1-methyl-1H-pyrazol-5- 467 [MH]+yl)phenoxy]-N-(5-fluoro-1,3-thiazol-2- yl)benzenesulfonamide 3484-{4-[1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5- 529 [MH]−yl]phenoxy}-3-fluoro-N-(5-fluoro-1,3-thiazol-2- yl)benzenesulfonamide349 4-[4-chloro-2-(1-methyl-1H-1,2,4-triazol-5- 484 [M³⁵ClH]+yl)phenoxy]-3-fluoro-N-(5-fluoro-1,3-thiazol-2- yl)benzenesulfonamide350 3-cyano-4-[4-ethyl-2-(1-methyl-1H-pyrazol-5- 466 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 3513-cyano-4-[4-isopropyl-2-(1-methyl-1H-pyrazol- 480 [MH]+5-yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 3523-cyano-4-{2-isopropyl-4-[3-(trifluoromethyl)- 534 [MH]+1H-pyrazol-1-yl]phenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 3534-[4-(4-chloro-1H-pyrazol-1-yl)-2- 500 [M³⁵ClH]+isopropylphenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 3543-cyano-4-{2-isopropyl-4-[1-methyl-3- 548 [MH]+(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2-ylbenzenesulfonamide 3554-[4-bromo-2-(pyrrolidin-1-ylmethyl)phenoxy]- 519 [M⁷⁹BrH]+3-cyano-N-1,3-thiazol-2-ylbenzenesulfonamide 3563-cyano-4-{2-isopropyl-4-[5-methyl-3- 548 [MH]+(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}-N-1,3-thiazol-2-ylbenzenesulfonamide 3574-{4-chloro-2-[(3-hydroxypyrrolidin-1- 491 [M³⁵ClH]+yl)methyl]phenoxy}-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 3584-{4-chloro-2-[(4,4-difluoropiperidin-1- 525 [M³⁵ClH]+yl)methyl]phenoxy}-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 3593-cyano-4-[5-iodo-2-(1-methyl-1H-pyrazol-5- 564 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 3604-{4-chloro-2-[(3,3-difluoropyrrolidin-1- 511 [M³⁵ClH]+yl)methyl]phenoxy}-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 3614-[4-chloro-2-(1-methyl-1H-pyrazol-5- 467 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-pyrimidin-4- ylbenzenesulfonamide 3624-[4-chloro-2-(1-methyl-1H-pyrazol-5- 454 [M³⁵ClH]−yl)phenoxy]-3-cyano-N-isoxazol-3- ylbenzenesulfonamide 3634-[4-chloro-2-(1-methyl-1H-pyrazol-5- 473 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 3645-chloro-2-fluoro-4-(4-fluoro-2-(1-methyl-1H- 484 [M³⁵ClH]+pyrazol-5-yl)phenoxy)-N-(1,2,3-thiadiazol-4- yl)benzenesulfonamide 3653-fluoro-4-[2-(1-methyl-1H-pyrazol-5-yl)-4- 515 [MH]+(trifluoromethoxy)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 3664-(biphenyl-2-yloxy)-3-cyano-N-(5- 446 [MH]+fluoropyridin-2-yl)benzenesulfonamide 3673-cyano-4-{4-[1-ethyl-3-(trifluoromethyl)-1H- 532 [MH]+pyrazol-5-yl]phenoxy}-N-(5-fluoropyridin-2- yl)benzenesulfonamide 3683-cyano-4-{3-[1-ethyl-3-(trifluoromethyl)-1H- 532 [MH]+pyrazol-5-yl]phenoxy}-N-(5-fluoropyridin-2- yl)benzenesulfonamide 3693-cyano-4-[4-(3-cyclopropyl-1-ethyl-1H-pyrazol- 492 [MH]+5-yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamid 3703-cyano-4-[4-(3-cyclopropyl-1H-pyrazol-1- 464 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 3713-cyano-4-{4-[1-methyl-5-(trifluoromethyl)-1H- 506 [MH]+pyrazol-3-yl]phenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 3723-cyano-4-[4-(5-cyclopropyl-1-ethyl-1H-pyrazol- 492 [MH]+3-yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 3734-[3-chloro-4-(3-cyclopropyl-1H-pyrazol-5- 498 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 3743-cyano-4-{4-[1-(2-hydroxyethyl)-3-methyl-1H- 482 [MH]+pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 3751-(4-{2-cyano-4-[(1,3-thiazol-2- 495 [MH]+ylamino)sulfonyl]phenoxy}phenyl)-N,N- dimethyl-1H-pyrazole-4-carboxamide376 3-cyano-4-{4-[4-(methoxymethyl)-1H-pyrazol-1- 468 [MH]+yl]phenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 3773-cyano-4-(4-{4-[(dimethylamino)methyl]-1H- 481 [MH]+pyrazol-1-yl}phenoxy)-N-1,3-thiazol-2- ylbenzenesulfonamide 378N-tert-butyl-1-(4-{2-cyano-4-[(1,3-thiazol-2- 523 [MH]+ylamino)sulfonyl]phenoxy}phenyl)-1H-pyrazole- 4-carboxamide 3791-(4-{2-cyano-4-[(1,3-thiazol-2- 467 [MH]+ylamino)sulfonyl]phenoxy}phenyl)-1H-pyrazole- 4-carboxamide 3804-{3-chloro-4-[3-(trifluoromethyl)-1H-pyrazol-1- 526 [M³⁵ClH]+yl]phenoxy}-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 3813-cyano-4-{3-fluoro-4-[3-(trifluoromethyl)-1H- 510 [MH]+pyrazol-1-yl]phenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 3823-cyano-4-{4-[1-(2-hydroxyethyl)-3- 536 [MH]+(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2-ylbenzenesulfonamide 3833-cyano-4-{4-[3-(difluoromethyl)-1-methyl-1H- 488 [MH]+pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 2844-[3-chloro-4-(4-chloro-1H-pyrazol-1- 492 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 3854-(2-(1H-pyrazol-4-yl)phenoxy)-3-cyano-N- 425 [MH]+(1,2,4-thiadiazol-5-yl)benzenesulfonamide 3863-cyano-4-[4-fluoro-2-(1-methyl-1H-pyrazol-5- 474 [MH]+yl)phenoxy]-N-(5-fluoro-1,3-thiazol-2- yl)benzenesulfonamide 3873-cyano-N-(5-fluoro-1,3-thiazol-2-yl)-4-{4-[1- 524 [MH]+methyl-3-(trifluoromethyl)-1H-pyrazol-5- yl]phenoxy}benzenesulfonamide388 3-cyano-4-[4-(1-ethyl-3-methyl-1H-pyrazol-5- 466 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 3893-cyano-4-[4-(1,3-dimethyl-1H-pyrazol-4- 452 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 3903-cyano-4-{3-[3-(difluoromethyl)-5- 504 [MH]+(hydroxymethyl)-1H-pyrazol-1-yl]phenoxy}-N-1,3-thiazol-2-ylbenzenesulfonamide 3913-cyano-4-[4-iodo-2-(1H-pyrazol-5-yl)phenoxy]- 550 [MH]+N-1,3-thiazol-2-ylbenzenesulfonamide 3924-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-3- 484 [M³⁵ClH]+cyano-N-1,3-thiazol-4-ylbenzenesulfonamide 3934-[2-(5-amino-1H-pyrazol-4-yl)-4- 473 [M³⁵ClH]+chlorophenoxy]-3-cyano-N-1,3-thiazol-4- ylbenzenesulfonamide 3944-{4-chloro-2-[1-(difluoromethyl)-1H-pyrazol-4- 508 [M³⁵ClH]+yl]phenoxy}-3-cyano-N-1,3-thiazol-4- ylbenzenesulfonamide 3954-{4-chloro-2-[1-methyl-3-(trifluoromethyl)-1H- 540 [M³⁵ClH]+pyrazol-5-yl]phenoxy}-3-cyano-N-1,3-thiazol-4- ylbenzenesulfonamide 3963-cyano-4-[4-fluoro-2-(3-isopropoxy-1-methyl- 514 [MH]+1H-pyrazol-5-yl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 3974-{4-chloro-2-[4-(trifluoromethyl)-1H-imidazol- 526 [M³⁵ClH]+1-yl]phenoxy}-3-cyano-N-1,3-thiazol-4- ylbenzenesulfonamide 3984-{4-chloro-2-[1-(trifluoromethyl)-1H-pyrazol-3- 526 [M³⁵ClH]+yl]phenoxy}-3-cyano-N-1,3-thiazol-4- ylbenzenesulfonamide 3994-{4-chloro-2-[1-(trifluoromethyl)-1H-pyrazol-5- 526 [M³⁵ClH]+yl]phenoxy}-3-cyano-N-1,3-thiazol-4- ylbenzenesulfonamide 4003-cyano-4-[2-(1-methyl-1H-pyrazol-5- 438 [MH]+yl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 4013-cyano-4-{4-[1-ethyl-3-(trifluoromethyl)-1H- 520 [MH]+pyrazol-5-yl]phenoxy}-N-1,3-thiazol-4- ylbenzenesulfonamide 4024-{4-chloro-2-[1-(difluoromethyl)-1H-pyrazol-5- 508 [M³⁵ClH]+yl]phenoxy}-3-cyano-N-1,3-thiazol-4- ylbenzenesulfonamide 4034-[2-(6-aminopyridin-2-yl)-4-chlorophenoxy]-5- 512 [M³⁵ClH]+chloro-2-fluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 4045-chloro-4-{4-[1-ethyl-3-(trifluoromethyl)-1H- 559 [M³⁵ClH]+pyrazol-5-yl]phenoxy}-2-fluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide 4054-[2-(2-aminopyridin-4-yl)-4-fluorophenoxy]-5- 496 [M³⁵ClH]+chloro-2-fluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 4064-[4-chloro-2-(1-methyl-1H-1,2,4-triazol-5- 466 [M³⁵ClH]+yl)phenoxy]-3-fluoro-N-1,3-thiazol-2- ylbenzenesulfonamide 4074-[2-(6-aminopyridin-2-yl)-4-fluorophenoxy]- 480 [MH]+2,5-difluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 4084-{4-[1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5- 513 [MH]+yl]phenoxy}-3-fluoro-N-1,3-thiazol-2- ylbenzenesulfonamide 4094-[2-(6-aminopyridin-2-yl)-4-chlorophenoxy]- 496 [M³⁵ClH]+2,5-difluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 4104-[2-(6-aminopyridin-3-yl)-4-chlorophenoxy]- 496 [M³⁵ClH]+2,5-difluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 4114-[2-(5-aminopyridin-2-yl)-4-chlorophenoxy]- 496 [M³⁵ClH]+2,5-difluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 4125-chloro-4-[4-(difluoromethoxy)-2-piperidin-4- 535.0 [M³⁵ClH]+ylphenoxy]-2-fluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 4134-[4-chloro-2-(1-methyl-1H-pyrazol-5- 506 [M³⁵ClH]+yl)phenoxy]-N-(5-chloro-1,3-thiazol-4-yl)-3- cyanobenzenesulfonamide 4144-[4-chloro-2-(1-methyl-1H-pyrazol-4- 472 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-4- ylbenzenesulfonamide 4154-{4-fluoro-2-[1-(2,2,2-trifluoroethyl)-1H- 524 [MH]+pyrazol-4-yl]phenoxy}-3-cyano-N-1,3-thiazol-4- ylbenzenesulfonamide 4164-(4-chloro-2-(1H-tetrazol-1-yl)phenoxy)-3- 460 [M³⁵ClH]+cyano-N-(thiazol-2-yl)benzenesulfonamide 4174-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-3- 485 [M³⁵ClH]+cyano-N-1,2,4-thiadiazol-5- 487 [M³⁷ClH]+ ylbenzenesulfonamide 4184-[4-chloro-3-(1H-imidazol-1- 472 [M³⁵ClH]+ylmethyl)phenoxy]-3-cyano-N-1,3-thiazol-4- ylbenzenesulfonamide 4194-{3-[(1-tert-butyl-1H-pyrazol-4- 494 [MH]+yl)methyl]phenoxy}-3-cyano-N-1,3-thiazol-4- ylbenzenesulfonamide 4204-(biphenyl-2-yloxy)-3-cyano-N-(3- 446 [MH]+fluoropyridin-2-yl)benzenesulfonamide 4214-(biphenyl-2-yloxy)-3-cyano-N-(6- 453 [MH]+cyanopyridin-2-yl)benzenesulfonamide 4224-(biphenyl-2-yloxy)-3-cyano-N-(4- 453 [MH]+cyanopyridin-2-yl)benzenesulfonamide 4234-(biphenyl-2-yloxy)-3-cyano-N-(5- 451 [MH]−cyanopyridin-2-yl)benzenesulfonamide 4244-(biphenyl-2-yloxy)-3-cyano-N-(5- 442 [MH]+methylpyridin-2-yl)benzenesulfonamide 4254-(biphenyl-2-yloxy)-3-cyano-N-(4- 443 [MH]+methylpyrimidin-2-yl)benzenesulfonamide 4264-(biphenyl-2-yloxy)-N-(2-chloropyrimidin-5- 463 [M³⁵ClH]+yl)-3-cyanobenzenesulfonamide 427 4-(biphenyl-2-yloxy)-3-cyano-N-(5- 447[MH]+ fluoropyrimidin-2-yl)benzenesulfonamide 4284-(biphenyl-2-yloxy)-3-cyano-N-(5- 443 [MH]+methylpyrimidin-4-yl)benzenesulfonamide 4294-(biphenyl-2-yloxy)-3-cyano-N-(5- 443 [MH]+methylpyrimidin-2-yl)benzenesulfonamide 4304-(biphenyl-2-yloxy)-N-(5-chloropyrimidin-2- 463 [M³⁵ClH]+yl)-3-cyanobenzenesulfonamide 4314-(biphenyl-2-yloxy)-3-cyano-N-1H-1,2,4- 418 [MH]+triazol-5-ylbenzenesulfonamide 432 4-(biphenyl-2-yloxy)-3-cyano-N-(5-452 [MH]− cyanopyrimidin-2-yl)benzenesulfonamide 4334-(biphenyl-2-yloxy)-3-cyano-N-(4- 454 [MH]+cyanopyrimidin-2-yl)benzenesulfonamide 4344-(biphenyl-2-yloxy)-3-cyano-N-[4- 497 [MH]+(trifluoromethyl)pyrimidin-2- yl]benzenesulfonamide 4354-[2-fluoro-4-(3-methoxy-1-methyl-1H-pyrazol- 486 [MH]+5-yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 4363-cyano-4-[4-(1-methyl-1H-pyrazol-5- 438 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 4373-cyano-4-[2-(1-methyl-1H-pyrazol-5-yl)-4- 507 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 4383-cyano-4-[2-(1H-pyrazol-4-yl)-4- 493 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 4394-[4-chloro-2-(3-methoxy-1-methyl-1H-pyrazol- 502 [M³⁵ClH]+5-yl)phenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 4403-cyano-4-[2-(1-methyl-1H-pyrazol-5-yl)-4- 506 [MH]+(trifluoromethyl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 441N-(5-chloro-1,3-thiazol-2-yl)-4-[4-cyano-2-(1- 508 [M³⁵ClH]+methyl-1H-pyrazol-5-yl)phenoxy]-2,5- difluorobenzenesulfonamide 4424-[4-chloro-2-(1-methyl-1H-pyrazol-5- 466 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-pyridin-2- ylbenzenesulfonamide 4434-[3-chloro-4-(1-methyl-1H-pyrazol-5- 472 [M³⁵ClH]⁺yl)phenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 4443-cyano-4-[3-(1H-pyrazol-5-yl)phenoxy]-N-1,3- 424 [MH]+thiazol-2-ylbenzenesulfonamide 445 3-cyano-4-[3-(1-methyl-1H-pyrazol-5-438 [MH]+ yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 4464-[4-chloro-3-(1H-pyrazol-5-yl)phenoxy]-3- 458 [M³⁵ClH]+cyano-N-1,3-thiazol-2-ylbenzenesulfonamide 4473-cyano-N-1,3-thiazol-2-yl-4-{3-[4- 503 [MH]+(trifluoromethyl)pyridin-2- yl]phenoxy}benzenesulfonamide 4483-cyano-N-1,3-thiazol-2-yl-4-{3-[6- 503 [MH]+(trifluoromethyl)pyridin-2- yl]phenoxy}benzenesulfonamide 4493-cyano-4-(3-pyridin-2-ylphenoxy)-N-1,3- 435 [MH]+thiazol-2-ylbenzenesulfonamide 4503-cyano-4-[4-(4-methylpyridin-2-yl)phenoxy]-N- 449 [MH]+1,3-thiazol-2-ylbenzenesulfonamide 4513-cyano-4-[4-(6-methoxypyridin-2-yl)phenoxy]- 465 [MH]+N-1,3-thiazol-2-ylbenzenesulfonamide 4523-cyano-N-1,3-thiazol-2-yl-4-{4-[5- 501 [MH]−(trifluoromethyl)pyridin-2- yl]phenoxy}benzenesulfonamide 4533-cyano-N-1,3-thiazol-2-yl-4-{4-[6- 503 [MH]+(trifluoromethyl)pyridin-2- yl]phenoxy}benzenesulfonamide 4543-cyano-N-1,3-thiazol-2-yl-4-{4-[4- 504 [MH]+(trifluoromethyl)pyrimidin- 2-yl]phenoxy}benzenesulfonamide 4553-cyano-4-[4-(3-methylpyridin-2-yl)phenoxy]-N- 449 [MH]+1,3-thiazol-2-ylbenzenesulfonamide 4564-[4-(3-chloropyridin-2-yl)phenoxy]-3-cyano-N- 469 [M³⁵ClH]⁺1,3-thiazol-2-ylbenzenesulfonamide 4573-cyano-N-1,3-thiazol-2-yl-4-{4-[3- 503 [MH]+(trifluoromethyl)pyridin-2- yl]phenoxy}benzenesulfonamide 4583-cyano-5-fluoro-4-[4-fluoro-2-(1H-pyrazol-4- 459 [MH]−yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 4593-cyano-5-fluoro-4-[4-fluoro-2-(1H-pyrazol-5- 461 [MH]+yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 4604-(2-(1H-pyrazol-4-yl)-4- 492 [MH]+(trifluoromethyl)phenoxy)-3-cyano-N-(thiazol-2- yl)benzenesulfonamide461 4-[4-bromo-2-(1H-pyrazol-5-yl)phenoxy]-3- 502 [M⁷⁹BrH]+cyano-N-1,3-thiazol-2-ylbenzenesulfonamide 4624-[4-chloro-2-(1-methyl-1H-pyrazol-5- 535 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-[5-(trifluoro-methyl)pyrimidin-2-yl]benzenesulfonamide 4634-[4-chloro-2-(1-methyl-1H-pyrazol-5- 492 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-(5-cyanopyrimidin-2- yl)benzenesulfonamide 4644-[4-chloro-2-(1-methyl-1H-pyrazol-5- 503 [M³⁵ClH]+yl)phenoxy]-N-(5-chloropyrimidin-2-yl)-3- cyanobenzenesulfonamide 4654-[4-chloro-2-(1-methyl-1H-pyrazol-5- 485 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-(5-fluoropyrimidin-2- yl)benzenesulfonamide 4664-[4-chloro-2-(1-methyl-1H-pyrazol-5- 491 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-(5-cyanopyridin-2- yl)benzenesulfonamide 4674-[2-(5-amino-1H-pyrazol-4-yl)-4- 518 [M³⁵ClH]+chlorophenoxy]-N-(5-chloro-1,3-thiazol-2-yl)-2,5-difluorobenzenesulfonamide 4682,5-difluoro-4-[2-(1-methyl-1H-pyrazol-5-yl)-4- 518 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 4693-cyano-4-[4-(1H-pyrazol-1-yl)phenoxy]-N-1,3- 424 [MH]+thiazol-2-ylbenzenesulfonamide 4703-cyano-4-[4-(1,4-dimethyl-1H-pyrazol-3- 452 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 4713-cyano-4-{4-[1-(difluoromethyl)-4-methyl-1H- 488 [MH]+pyrazol-3-yl]phenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 4723-cyano-4-{2,3-difluoro-5-[1-methyl-3- 542 [MH]+(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2-ylbenzenesulfonamide 4733-chloro-4-{4-[1-ethyl-3-(trifluoromethyl)-1H- 530 [M³⁵ClH]+pyrazol-5-yl]phenoxy}-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 4744-[2-(1-tert-butyl-1H-pyrazol-5-yl)-4- 524 [M³⁵ClH]+chlorophenoxy]-3-chloro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 4753-chloro-4-[4-chloro-2-(1H-pyrazol-5- 468 [M³⁵ClH]+yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 4764-[2-(1-tert-butyl-1H-pyrazol-5-yl)-4- 508 [M³⁵ClH]+fluorophenoxy]-3-chloro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 4773-chloro-4-(4-chloro-2-piperidin-4-ylphenoxy)- 485 [M³⁵ClH]+N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 4783-chloro-4-[4-fluoro-2-(1H-pyrazol-5- 452 [M³⁵ClH]+yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 4793-cyano-4-{3-[1-ethyl-3-(trifluoromethyl)-1H- 538 [MH]+pyrazol-5-yl]phenoxy}-N-(5-fluoro-1,3-thiazol- 2-yl)benzenesulfonamide480 3-cyano-4-{2-fluoro-4-[1-(3-fluoropropyl)-5- 570 [MH]+(trifluoromethyl)-1H-pyrazol-3-yl]phenoxy}-N-1,3-thiazol-2-ylbenzenesulfonamide 4813-cyano-4-(3-{1-[2-(dimethylamino)ethyl]-3- 509 [MH]+methyl-1H-pyrazol-5-yl}phenoxy)-N-1,3-thiazol- 2-ylbenzenesulfonamide482 4-{4-[3-amino-1-(2,2,2-trifluoroethyl)-1H- 521 [MH]+pyrazol-4-yl]phenoxy}-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 4834-[4-(3-amino-1-methyl-1H-pyrazol-4- 453 [MH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 4843-cyano-4-[4-(4-methyl-2-oxoimidazolidin-1- 456 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 4853-cyano-4-[4-(4-isopropyl-2-oxoimidazolidin-1- 484 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 4863-cyano-4-[4-(2-oxoimidazolidin-1-yl)phenoxy]- 442 [MH]+N-1,3-thiazol-2-ylbenzenesulfonamide 4873-cyano-4-[4-(3-methyl-2-oxoimidazolidin-1- 456 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 4883-cyano-4-[4-(2-oxopyrrolidin-1-yl)phenoxy]-N- 441 [MH]+1,3-thiazol-2-ylbenzenesulfonamide 4893-cyano-4-[2-ethyl-4-(1H-pyrazol-1-yl)phenoxy]- 452 [MH]+N-1,3-thiazol-2-ylbenzenesulfonamide 4903-cyano-4-{2-ethyl-4-[3-(trifluoromethyl)-1H- 520 [MH]+pyrazol-1-yl]phenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 4913-cyano-4-[4-(1H-pyrazol-1-yl)-2- 492 [MH]+(trifluoromethyl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 4923-cyano-N-1,3-thiazol-2-yl-4-{2- 560 [MH]+(trifluoromethyl)-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}benzenesulfonamide 4934-[4-chloro-2-(morpholin-4-ylmethyl)phenoxy]- 491 [M³⁵ClH]+3-cyano-N-1,3-thiazol-2-ylbenzenesulfonamide 4943-cyano-4-[5-fluoro-2-(1-methyl-1H-pyrazol-3- 456 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 495 methyl2-(4-chloro-1H-pyrazol-1-yl)-5-{2-cyano- 516 [M³⁵ClH]+4-[(1,3-thiazol-2- ylamino)sulfonyl]phenoxy}benzoate 4964-[4-(4-chloro-1H-pyrazol-1-yl)-3- 502 [M³⁵ClH]+(methoxymethyl)phenoxy]-3-cyano-N-1,3- thiazol-2-ylbenzenesulfonamide497 2-(4-chloro-1H-pyrazol-1-yl)-5-{2-cyano-4-[(1,3- 502 [M³⁵ClH]+thiazol-2-ylamino)sulfonyl]phenoxy}benzoic acid 4984-[4-chloro-2-(1H-pyrazol-5-yl)phenoxy]-3- 459 [M³⁵ClH]+cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 4993-cyano-4-[4-fluoro-2-(1H-pyrazol-5- 443 [MH]+yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 5003-cyano-4-{4-[1-ethyl-3-(trifluoromethyl)-1H- 521 [MH]+pyrazol-5-yl]phenoxy}-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 5014-[4-bromo-2-(1-methyl-1H-pyrazol-5- 517 [M⁷⁹BrH]+yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 5023-cyano-4-[2-(1H-pyrazol-4-yl)-4- 509 [MH]+(trifluoromethoxy)phenoxy]-N-1,2,4-thiadiazol- 5-ylbenzenesulfonamide503 4-[Bromo-2-(1H-pyrazol-4-yl)phenoxy]-3-cyano- 503 [M⁷⁹BrH]+N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 505 [M⁸¹BrH]+ 5044-[(3′-acetyl-5-chlorobiphenyl-2-yl)oxy]-3- 511 [M³⁵ClH]+cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 5054-(4-chloro-2-piperidin-4-ylphenoxy)-3-cyano-N- 476 [M³⁵ClH]+1,2,4-thiadiazol-5-ylbenzenesulfonamide 5063-cyano-4-[4-iodo-2-(1H-pyrazol-5-yl)phenoxy]- 551 [MH]+N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 5073-cyano-4-[5-iodo-2-(1-methyl-1H-pyrazol-5- 565 [MH]+yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 5083-cyano-4-[2-(2-methylpyridin-4-yl)-4- 518 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 5093-cyano-4-{[3′-cyano-5- 528 [MH]+(trifluoromethyl)biphenyl-2-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 5104-{4-chloro-2-[1-(difluoromethyl)-1H-pyrazol-5- 509 [M³⁵ClH]+yl]phenoxy}-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 5114-{[3′-(aminomethyl)-5-chlorobiphenyl-2- 498 [M³⁵ClH]+yl]oxy}-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 512N-(5-Bromo-1,3-thiazol-2-yl)-3-cyano-4-[(3,5- 668 [M⁷⁹BrH]+dibromobiphenyl-2-yl)oxy]benzenesulfonamide 5134-[4-chloro-2-(1-methyl-1H-pyrazol-5- 466 [M³⁵ClH]+yl)phenoxy]-3-fluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 5144-[4-chloro-2-(1-methyl-1H-pyrazol-5- 477 [M³⁵ClH]+yl)phenoxy]-3-fluoro-N-(5-fluoropyridin-2- yl)benzenesulfonamide 5154-[4-chloro-2-(1-methyl-1H-pyrazol-5- 480 [M³⁵ClH]+yl)phenoxy]-3-fluoro-N-(3-methyl-1,2,4-thiadiazol-5-yl)benzenesulfonamide 516 tert-Butyl [(5-chloro-2,4- 508[M³⁵ClH]+ difluorophenyl)sulfonyl](5-cyano-1,3-thiazol-4- yl)carbamate517 5-chloro-2-fluoro-4-{4-fluoro-2-[1-(2- 513 [M³⁵ClH]+hydroxyethyl)-1H-pyrazol-5-yl]phenoxy}-N-1,3-thiazol-4-ylbenzenesulfonamide 5185-chloro-2-fluoro-4-[2-pyrimidin-5-yl-5- 531 [M³⁵ClH]+(trifluoromethyl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 5194-[2-(1-tert-butyl-1H-pyrazol-5-yl)-4- 525 [M³⁵ClH]+fluorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol- 4-ylbenzenesulfonamide520 4-[2-(1-tert-butyl-1H-pyrazol-3-yl)-4- 525 [M³⁵ClH]+fluorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol- 4-ylbenzenesulfonamide521 5-chloro-2-fluoro-4-[4-fluoro-2-(1H-1,2,3- 470 [M³⁵ClH]+triazol-4-yl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 5225-chloro-2-fluoro-4-[4-fluoro-2-(1-methyl-1H- 483 [M³⁵ClH]+pyrazol-3-yl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 5235-chloro-2-fluoro-4-[4-fluoro-2-(1-methyl-1H- 484 [M³⁵ClH]+1,2,3-triazol-5-yl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 5245-chloro-4-{2-cyano-4-[1-methyl-3- 558 [M³⁵ClH]+(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide 5253-cyano-N-1,3-thiazol-2-yl-4-{4-[4- 501 [MH]−(trifluoromethyl)pyridin-2- yl]phenoxy}benzenesulfonamide 5263-cyano-4-[4,5-difluoro-2-(1-methyl-1H-pyrazol- 474 [MH]+5-yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 5273-cyano-4-{2-fluoro-3-[1-methyl-3- 524 [MH]+(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2-ylbenzenesulfonamide 5283-fluoro-4-[4-fluoro-2-(1-methyl-1H-pyrazol-5- 444 [MH]+yl)phenoxy]-N-pyrimidin-4- ylbenzenesulfonamide 5294-(Biphenyl-2-yloxy)-3-cyano-N-(5-fluoro-1,3- 450 [MH]−thiazol-2-yl)benzenesulfonamide 530 4-[4-chloro-3-(1H-imidazol-1- 490[M³⁵ClH]+ ylmethyl)phenoxy]-3-cyano-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide 5314-[(6-chloro-3′-methoxybiphenyl-3-yl)oxy]-3- 516 [M³⁵ClH]+cyano-N-(5-fluoro-1,3-thiazol-2- yl)benzenesulfonamide 5324-{[6-chloro-3′-(methoxymethyl)biphenyl-3- 530 [M³⁵ClH]+yl]oxy}-3-cyano-N-(5-fluoro-1,3-thiazol-2- yl)benzenesulfonamide 5334-[4-chloro-3-(1H-1,2,3-triazol-1- 491 [M³⁵ClH]+ylmethyl)phenoxy]-3-cyano-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide 5344-[4-chloro-3-(1H-pyrazol-1-ylmethyl)phenoxy]- 490 [M³⁵ClH]+3-cyano-N-(5-fluoro-1,3-thiazol-2- yl)benzenesulfonamide 5353-cyano-4-{2-fluoro-4-[1-methyl-3- 542 [MH]+(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide 5363-cyano-4-{4-[1-ethyl-3-(trifluoromethyl)-1H- 556 [MH]+pyrazol-5-yl]-3-fluorophenoxy}-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide 5373-cyano-4-{4-[1-ethyl-3-(trifluoromethyl)-1H- 556 [MH]+pyrazol-5-yl]-2-fluorophenoxy}-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide 5383-cyano-4-[2-cyano-4-(1-methyl-1H-pyrazol-5- 481 [MH]+yl)phenoxy]-N-(5-fluoro-1,3-thiazol-2- yl)benzenesulfonamide 5393-cyano-N-(5-fluoro-1,3-thiazol-2-yl)-4-[2- 468 [MH]−methyl-4-(1-methyl-1H-pyrazol-5- yl)phenoxy]benzenesulfonamide 5403-cyano-4-{4-[1-ethyl-5-(trifluoromethyl)-1H- 556 [MH]+pyrazol-3-yl]-2-fluorophenoxy}-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide 5413-cyano-4-[5-methoxy-2-(1-methyl-1H-pyrazol- 468 [MH]+5-yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 5423-cyano-4-[5-fluoro-2-(1-methyl-1H-pyrazol-5- 456 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 5433-cyano-4-[5-methyl-2-(1-methyl-1H-pyrazol-5- 452 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 5444-[5-chloro-2-(1-methyl-1H-pyrazol-5- 472 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 5453-cyano-4-[4-cyclopropyl-2-(1-methyl-1H- 478 [MH]+pyrazol-5-yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 5464-[4-chloro-2-(5-methyl-1H-pyrazol-4- 472 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 5473-cyano-4-{3-[1-ethyl-3-(trifluoromethyl)-1H- 520 [MH]+pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 5483-cyano-4-{4-[3-(1-cyano-1-methylethyl)-1- 519 [MH]+ethyl-1H-pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 5493-cyano-4-{3-[1-(2-hydroxyethyl)-3- 536 [MH]+(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2-ylbenzenesulfonamide 5503-cyano-4-(3-{1-[2-(dimethylamino)ethyl]-3- 563 [MH]+(trifluoromethyl)-1H-pyrazol-5-yl}phenoxy)-N-1,3-thiazol-2-ylbenzenesulfonamide 5513-cyano-4-{2-fluoro-4-[1-(3-fluoropropyl)-3- 570 [MH]+(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2-ylbenzenesulfonamide 552 4-[2-(2-aminopyridin-4-yl)-4- 547[MH]+ (trifluoromethoxy)phenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 5534-[2-(2-aminopyridin-4-yl)-4- 562 [M³⁵ClH]+(trifluoromethoxy)phenoxy]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 5544-[2-(4-aminopyridin-2-yl)-4-chlorophenoxy]-5- 512 [M³⁵ClH]+chloro-2-fluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 5554-[2-(6-aminopyridin-2-yl)-4- 530 [MH]+(trifluoromethyl)phenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 556 4-[2-(2-aminopyridin-4-yl)-4- 530[MH]+ (trifluoromethyl)phenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 557 4-[2-(2-aminopyridin-4-yl)-4- 546[M³⁵ClH]+ (trifluoromethyl)phenoxy]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 5584-{4-[1-azetidin-3-yl-3-(trifluoromethyl)-1H- 547 [MH]+pyrazol-5-yl]phenoxy}-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 5594-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4- 547 [M³⁵ClH]+chlorophenoxy]-N-(5-chloro-1,3-thiazol-2-yl)-3- cyanobenzenesulfonamide560 5-chloro-4-(4-chloro-2-piperidin-4-ylphenoxy)-2- 497 [M³⁵ClH]+fluoro-N-pyrimidin-4-ylbenzenesulfonamide 5614-(4-chloro-2-piperidin-4-ylphenoxy)-2,5- 498 [M³⁵ClH]+difluoro-N-(5-fluoropyridin-2- yl)benzenesulfonamide 5624-{4-chloro-2-[1-(2-methoxyethyl)-1H-pyrazol- 517 [M³⁵ClH]+5-yl]phenoxy}-3-cyano-N-1,2,4-thiadiazol-5- 519 [M³⁷ClH]+ylbenzenesulfonamide 563 5-chloro-4-{4-chloro-2-[1-(2-methoxyethyl)-1H-544 [M³⁵ClH]+ pyrazol-5-yl]phenoxy}-2-fluoro-N-1,3,4- 546 [M³⁷ClH]+thiadiazol-2-ylbenzenesulfonamide 5645-chloro-4-[4-chloro-2-(1H-pyrazol-4- 486 [M³⁵ClH]+yl)phenoxy]-2-fluoro-N-1,3,4-thiadiazol-2- 488 [M³⁷ClH]+ylbenzenesulfonamide 565 3-cyano-N-(5-fluoropyridin-2-yl)-4-{4-[(1,3,5-492 [MH]+ trimethyl-1H-pyrazol-4-yl) methyl]phenoxy}benzenesulfonamide566 4-[4-(azetidin-1-ylmethyl)-3-fluorophenoxy]-3- 457 [MH]+cyano-N-(5-fluoropyridin-2- yl)benzenesulfonamide 5673-cyano-N-(5-fluoropyridin-2-yl)-4-[4-(pyridin- 461 [MH]+3-ylmethyl)phenoxy]benzenesulfonamide 5683-cyano-4-[4-(3-ethyl-5-methyl-4H-1,2,4-triazol- 479 [MH]+4-yl)phenoxy]-N-(5-fluoropyridin-2- yl)benzenesulfonamide 5693-cyano-N-(5-fluoropyridin-2-yl)-4-[4-(1H- 436 [MH]+imidazol-1-yl)phenoxy]benzenesulfonamide 5703′-(2-cyano-4-{[(5-fluoropyridin-2- 517 [MH]+yl)amino]sulfonyl}phenoxy)-N-ethylbiphenyl-4- carboxamide 5713-cyano-N-(5-fluoropyridin-2-yl)-4-[2-(3- 467 [MH]+ methylisothiazol-5-yl)phenoxy]benzenesulfonamide 5723-cyano-N-(5-fluoropyridin-2-yl)-4-[2-(2-methyl- 467 [MH]+1,3-thiazol-4-yl)phenoxy]benzenesulfonamide 5733-cyano-N-(5-fluoropyridin-2-yl)-4-[3-(1- 467 [MH]+ methylpiperidin-4-yl)phenoxy]benzenesulfonamide 5743-cyano-N-(5-fluoropyridin-2-yl)-4-[3-(5-methyl- 452 [MH]+1,2,4-oxadiazol-3- yl)phenoxy]benzenesulfonamide 5753-cyano-N-(5-fluoropyridin-2-yl)-4-[3-methoxy- 480 [MH]+4-(4-methyl-1H-imidazol-1- yl)phenoxy]benzenesulfonamide 5763-cyano-N-(5-fluoropyridin-2-yl)-4-[4-(5-methyl- 452 [MH]+1,3,4-oxadiazol-2- yl)phenoxy]benzenesulfonamide 5773-cyano-N-(5-fluoropyridin-2-yl)-4-[2-(4- 467 [MH]+ methylisothiazol-5-yl)phenoxy]benzenesulfonamide 5783-cyano-N-(5-fluoropyridin-2-yl)-4-[3-methoxy- 480 [MH]+4-(2-methyl-1H-imidazol-1- yl)phenoxy]benzenesulfonamide 5793-cyano-N-(5-fluoropyridin-2-yl)-4-[3-methoxy- 466 [MH]+4-(1H-pyrazol-1-yl)phenoxy]benzenesulfonamide 5803-cyano-N-(5-fluoropyridin-2-yl)-4-[2-(1,3,4- 438 [MH]+oxadiazol-2-yl)phenoxy]benzenesulfonamide 5813-cyano-N-(5-fluoropyridin-2-yl)-4-[4-(1,3- 437 [MH]+oxazol-4-yl)phenoxy]benzenesulfonamide 5824-[4-Chloro-2-(1H-pyrazol-4-yl)phenoxy]-3- 584 [M³⁵ClH]+cyano-N-(5-iodo-1,3-thiazol-2- yl)benzenesulfonamide 5834-[2-(5-Amino-1H-pyrazol-4-yl)-4- 507 [M³⁵ClH]+chlorophenoxy]-N-(5-chloro-1,3-thiazol-2-yl)-3- cyanobenzenesulfonamide584 4-[2-(2-Aminopyridin-4-yl)-4-fluorophenoxy]-N- 502 [M³⁵ClH]+(5-chloro-1,3-thiazol-2-yl)-3- cyanobenzenesulfonamide 5854-[2-(2-Aminopyridin-4-yl)-4-chlorophenoxy]-N- 516 [M³⁵ClH]−(5-chloro-1,3-thiazol-2-yl)-3- cyanobenzenesulfonamide 5864-{4-Chloro-2-[2-(hydroxymethyl)pyridin-4- 533.0 [M³⁵ClH]+yl]phenoxy}-N-(5-chloro-1,3-thiazol-2-yl)-3- cyanobenzenesulfonamide 5874-[2-(6-Aminopyridin-3-yl)-4-fluorophenoxy]-N- 502 [M³⁵ClH]+(5-chloro-1,3-thiazol-2-yl)-3- cyanobenzenesulfonamide 5884-(4-Chloro-2-oxetan-3-ylphenoxy)-N-(5-chloro- 482 [M³⁵ClH]+1,3-thiazol-2-yl)-3-cyanobenzenesulfonamide 589N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-[4- 476 [M³⁵ClH]+fluoro-2-(1H-pyrazol-5- yl)phenoxy]benzenesulfonamide 590N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-[2-(1H- 526 [M³⁵ClH]+pyrazol-4-yl)-4- (trifluoromethyl)phenoxy]benzenesulfonamide 591N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-[2-(1H- 542 [M³⁵ClH]+pyrazol-4-yl)-4- (trifluoromethoxy)phenoxy]benzenesulfonamide 592N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-{[4-(1- 540 [M³⁵ClH]+methyl-1H-pyrazol-5-yl)-6-(trifluoro-methyl)pyridin-3-yl]oxy}benzenesulfonamide 5934-(4-Chloro-2-piperidin-4-ylphenoxy)-N-(5- 509 [M³⁵ClH]+chloro-1,3-thiazol-2-yl)-3- cyanobenzenesulfonamide 5944-(2-Azetidin-3-yl-4-chlorophenoxy)-N-(5- 481 [M³⁵ClH]+chloro-1,3-thiazol-2-yl)-3- cyanobenzenesulfonamide 5954-{4-Chloro-2-[1-(difluoromethyl)-1H-pyrazol-5- 542.0 [M³⁵ClH]+yl]phenoxy}-N-(5-chloro-1,3-thiazol-2-yl)-3- cyanobenzenesulfonamide 596N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-[4- 490 [M³⁵ClH]+fluoro-2-(1-methyl-1H-pyrazol-5- yl)phenoxy]benzenesulfonamide 5974-[4-Chloro-2-(1-methyl-1H-pyrazol-5- 506 [M³⁵ClH]+yl)phenoxy]-N-(5-chloro-1,3-thiazol-2-yl)-3- cyanobenzenesulfonamide 5983-cyano-4-[2-(1H-pyrazol-4-yl)-4- 492 [MH]+(trifluoromethyl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 5993-cyano-4-[2-(1H-pyrazol-4-yl)-4- 508 [MH]+(trifluoromethoxy)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 6004-(biphenyl-2-yloxy)-3-cyano-N-(5-methyl-1,3- 448 [MH]+thiazol-4-yl)benzenesulfonamide 6013-cyano-4-{[4-(1-methyl-1H-pyrazol-5-yl)-6- 507.0 [MH]+(trifluoromethyl)pyridin-3-yl]oxy}-N-1,3-thiazol- 4-ylbenzenesulfonamide602 4-[4-chloro-2-(1-methyl-1H-pyrazol-5- 490 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-(5-fluoro-1,3-thiazol-4- yl)benzenesulfonamide 6034-(biphenyl-2-yloxy)-3-cyano-N-1,2,4-thiadiazol- 433 [MH]−3-ylbenzenesulfonamide 604 4-(2-azetidin-3-yl-4-chlorophenoxy)-2,5- 458[M³⁵ClH]+ difluoro-N-1,3-thiazol-4-ylbenzenesulfonamide 6054-[4-chloro-2-(1H-pyrazol-4-yl)phenoxy]-2,5- 469 [M³⁵ClH]+difluoro-N-1,3-thiazol-4-ylbenzenesulfonamide 6064-[4-chloro-2-(1-methyl-1H-pyrazol-5- 483 [M³⁵ClH]+yl)phenoxy]-2,5-difluoro-N-1,3-thiazol-4- ylbenzenesulfonamide 6072,5-difluoro-4-[2-(1-methyl-1H-pyrazol-4-yl)-4- 533 [MH]+(trifluoromethoxy)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 6084-[4-chloro-2-(1-methyl-1H-pyrazol-5- 484 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-(5-fluoropyridin-2- yl)benzenesulfonamide 6093-fluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-{4-[1- 517 [MH]+methyl-3-(trifluoromethyl)-1H-pyrazol-5- yl]phenoxy}benzenesulfonamide610 4-[4-(3,5-Dimethyl-1H-pyrazol-1-yl)phenoxy]-2- 445 [MH]+fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide 6114-[4-chloro-2-(1H-pyrazol-4-yl)phenoxy]-3- 451 [M³⁵ClH]+fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide 6123-fluoro-4-[2-(1H-pyrazol-4-yl)-4- 501 [MH]+(trifluoromethoxy)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 613N-(5-chloro-1,3-thiazol-2-yl)-2,5-difluoro-4-[4- 501 [M³⁵ClH]+fluoro-2-(1-methyl-1H-pyrazol-5- yl)phenoxy]benzenesulfonamide 614N-(5-chloro-1,3-thiazol-2-yl)-2,5-difluoro-4-[4- 487 [M³⁵ClH]+fluoro-2-(1H-pyrazol-4- yl)phenoxy]benzenesulfonamide 615N-(5-chloro-1,3-thiazol-2-yl)-4-[5-cyano-2-(1- 508 [M³⁵ClH]+methyl-1H-pyrazol-5-yl)phenoxy]-2,5- difluorobenzenesulfonamide 6165-chloro-4-[2-(5-cyanopyridin-3-yl)-4- 556 [M³⁵ClH]+(trifluoromethyl)phenoxy]-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 6174-[2-(6-aminopyridin-2-yl)-4-fluorophenoxy]-5- 496 [M³⁵ClH]+chloro-2-fluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 6184-[2-(2-aminopyridin-3-yl)-4-chlorophenoxy]-5- 512 [M³⁵ClH]+chloro-2-fluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 6194-(2-azetidin-3-yl-4-chlorophenoxy)-5-chloro-2- 475 [M³⁵ClH]+fluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 6205-chloro-2-fluoro-4-[4-fluoro-2-(1H-pyrazol-5- 470 [M³⁵ClH]+yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 6215-chloro-2-fluoro-4-(4-fluoro-2-(1-methyl-1H- 484 [M³⁵ClH]+pyrazol-5-yl)phenoxy)-N-(1,2,4-thiadiazol-5- yl)benzenesulfonamide 6224-[2-(2-aminopyrimidin-4-yl)-4-fluorophenoxy]- 514 [M³⁵ClH]+N-(5-chloro-1,3-thiazol-2-yl)-2,5- difluorobenzenesulfonamide 6235-chloro-4-(4-chloro-2-piperidin-4-ylphenoxy)-2- 514 [M³⁵ClH]+fluoro-N-(5-fluoropyridin-2- yl)benzenesulfonamide 6245-chloro-4-[4-chloro-2-(1-methyl-1H-pyrazol-5- 509 [M³⁵ClH]+yl)phenoxy]-2-fluoro-N-(5-fluoropyridin-2- yl)benzenesulfonamide 6255-bromo-2-fluoro-4-[4-fluoro-2-(1-methyl-1H- 527 [M⁷⁹BrH]+pyrazol-5-yl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 6262-fluoro-4-[4-fluoro-2-(1-methyl-1H-pyrazol-5- 463 [MH]+yl)phenoxy]-5-methyl-N-1,3-thiazol-4- ylbenzenesulfonamide 6275-ethyl-2-fluoro-4-[4-fluoro-2-(1-methyl-1H- 477 [MH]+pyrazol-5-yl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 6283-methyl-4-[2-(1-methyl-1H-pyrazol-5- 427 [MH]+yl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 6293-iodo-4-[2-(1-methyl-1H-pyrazol-5- 539 [MH]+yl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 6305-chloro-2-fluoro-4-(4-fluoro-2-(1-methyl-1H- 497 [M³⁵ClH]+pyrazol-5-yl)phenoxy)-N-(5-methylthiazol-4- yl)benzenesulfonamide 6315-chloro-6-(4-chloro-2-(1-methyl-1H-pyrazol-5- 482 [M³⁵ClH]+yl)phenoxy)-N-(thiazol-4-yl)pyridine-3- sulfonamide 6322,5-difluoro-4-[2-pyrazin-2-yl-4- 516 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 6332,5-difluoro-4-[2-(tetrahydro-2H-pyran-4-yl)-4- 522 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 6344-[2-(2-aminopyridin-4-yl)-4-fluorophenoxy]- 480 [MH]+2,5-difluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 6354-[4-chloro-2-(5-methyl-1H-pyrazol-4- 484 [M³⁵ClH]+yl)phenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 6364-(4-chloro-2-piperidin-4-ylphenoxy)-2,5- 470 [M³⁵ClH]+difluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 6374-[4-Chloro-2-(1H-pyrazol-5-yl)phenoxy]-2,5- 470 [MH]+difluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 6384-(4-chloro-2-(1-methyl-1H-pyrazol-5- 484.0 [M³⁵ClH]⁺yl)phenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5- yl)benzenesulfonamide639 4-[3-(6-aminopyridin-2-yl)phenoxy]-3-cyano-N- 450 [MH]+1,3-thiazol-2-ylbenzenesulfonamide 6404-[2-(1-acetylazetidin-3-yl)-4-chlorophenoxy]-3- 489 [M³⁵ClH]+cyano-N-1,3-thiazol-2-ylbenzenesulfonamide 6413-cyano-4-{4-fluoro-2-[1-(2,2,2-trifluoroethyl)- 524 [MH]+1H-pyrazol-4-yl]phenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 6423-cyano-4-[2-fluoro-4-(1H-pyrazol-1- 456 [MH]+ylmethyl)phenoxy]-N-1,3-azol-2- ylbenzenesulfonamide 6433-cyano-N-1,3-thiazol-2-yl-4-({6-[3- 493 [MH]+(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3- yl}oxy)benzenesulfonamide644 3-cyano-4-[(6-phenoxypyridin-3-yl)oxy]-N-1,3- 451 [MH]+thiazol-2-ylbenzenesulfonamide 645 3-cyano-4-{[6-(1-methyl-1H-pyrazol-5-439 [MH]+ yl)pyridin-3-yl]oxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 6463-cyano-4-[(6-phenylpyridin-3-yl)oxy]-N-1,3- 435 [MH]+thiazol-2-ylbenzenesulfonamide 6473-cyano-4-({6-[1-methyl-3-(trifluoromethyl)-1H- 507 [MH]+pyrazol-5-yl]pyridin-3-yl}oxy)-N-1,3-thiazol-2- ylbenzenesulfonamide 6484-[4-chloro-3-(1-methyl-1H-pyrazol-5- 472 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 6493-cyano-N-1,3-thiazol-2-yl-4-{3-[3- 490 [MH]−(trifluoromethyl)-1H-pyrazol-1- yl]phenoxy}benzenesulfonamide 6503-cyano-4-{3-[5-methyl-3-(trifluoromethyl)-1H- 506 [MH]+pyrazol-1-yl]phenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 6514-[4-chloro-2-(1-methyl-1H-imidazol-2- 472 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 6524-(4-chloro-2-pyrazin-2-ylphenoxy)-3-cyano-N- 470 [M³⁵ClH]+1,3-thiazol-2-ylbenzenesulfonamide 6533-cyano-4-{3-fluoro-5-[1-methyl-3- 524 [MH]+(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2-ylbenzenesulfonamide 6543-cyano-4-{3-[3-(difluoromethyl)-5- 518 [MH]+(methoxymethyl)-1H-pyrazol-1-yl]phenoxy}-N-1,3-thiazol-2-ylbenzenesulfonamide 6555-chloro-4-(4-chloro-2-piperidin-4-ylphenoxy)-2- 502 [M³⁵ClH]+fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide 6565-chloro-2-fluoro-4-{[2-(1-methyl-1H-pyrazol-5- 534 [M³⁵ClH]+yl)-6-(trifluoromethyl)pyridin-3-yl]oxy}-N-1,3-thiazol-4-ylbenzenesulfonamide 6575-chloro-2-fluoro-4-[4-fluoro-2-(1-methyl-1H- 483 [M³⁵ClH]+pyrazol-5-yl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 6585-chloro-2-fluoro-4-[4-fluoro-2-(1H-pyrazol-5- 469 [M³⁵ClH]+yl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 6595-chloro-2-fluoro-4-[2-(1H-pyrazol-4-yl)-4- 519 [M³⁵ClH]+(trifluoromethyl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 6605-chloro-4-[4-chloro-2-(1-methyl-1H-pyrazol-5- 499 [M³⁵ClH]+yl)phenoxy]-2-fluoro-N-1,3-thiazol-4- ylbenzenesulfonamide 6615-chloro-4-[4-chloro-2-(1H-pyrazol-4- 485 [M³⁵ClH]+yl)phenoxy]-2-fluoro-N-1,3-thiazol-4- ylbenzenesulfonamide 6625-chloro-4-[4-chloro-2-(3-methyl-1H-pyrazol-4- 499 [M³⁵ClH]+yl)phenoxy]-2-fluoro-N-1,3-thiazol-4- ylbenzenesulfonamide 6635-chloro-2-fluoro-4-{[3′-(hydroxymethyl)-4- 559 [[M³⁵ClH]+(trifluoromethyl)biphenyl-2-yl]oxy}-N-1,3-thiazol-4-ylbenzenesulfonamide 6645-chloro-2-fluoro-4-[2-(1H-pyrazol-4-yl)-5- 518 [M³⁵ClH]+(trifluoromethyl)phenoxy]-N-1,3-thiazol-4- 520 [M³⁷ClH]+ylbenzenesulfonamide 665 3-Cyano-4-{4-[4-(hydroxymethyl)-1,3-oxazol-2-456 [MH]+ yl]phenoxy}-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 6662,5-Difluoro-N-(5-fluoropyridin-2-yl)-4-[2- 532 [MH]+ piperidin-4-yl-4-(trifluoromethyl)phenoxy]benzenesulfonamide 6674-[4-chloro-2-(1-methyl-1H-pyrazol-5- 495 [M³⁵ClH]+yl)phenoxy]-N-(3,5-difluoropyridin-2-yl)-3- fluorobenzenesulfonamide 6683-Chloro-4-[4-chloro-2-(1-methyl-1H-pyrazol-5- 476 [M³⁵ClH]+yl)phenoxy]-N-pyrimidin-4- ylbenzenesulfonamide 6693-Chloro-4-[4-fluoro-2-(1-methyl-1H-pyrazol-5- 460 [M³⁵ClH]+yl)phenoxy]-N-pyrimidin-4- ylbenzenesulfonamide 6704-[4-Chloro-2-(1-methyl-1H-pyrazol-5- 460 [M³⁵ClH]+yl)phenoxy]-3-fluoro-N-pyrimidin-4- ylbenzenesulfonamide 6713-cyano-4-[2-pyrazin-2-yl-4- 505 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 6724-[4-chloro-2-(1H-pyrazol-4-yl)phenoxy]-N-1,3- 433 [M³⁵ClH]+thiazol-4-ylbenzenesulfonamide 673 3-chloro-4-[4-chloro-2-(1H-pyrazol-4-467 [M³⁵ClH]+ yl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 6744-[4-chloro-2-(1H-pyrazol-4-yl)phenoxy]-3- 469 [M³⁵ClH]+fluoro-N-(5-fluoro-1,3-thiazol-2- yl)benzenesulfonamide 6753-cyano-5-fluoro-4-[4-fluoro-2-(1-methyl-1H- 475 [MH]+pyrazol-5-yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 6764-[4-chloro-2-(1H-pyrazol-4-yl)phenoxy]-3- 477 [M³⁵ClH]+cyano-5-fluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 6772,5-difluoro-4-[2-(1H-pyrazol-4-yl)-4- 519 [MH]+(trifluoromethoxy)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 6782,5-difluoro-4-{4-[1-methyl-3-(trifluoromethyl)- 517 [MH]+1H-pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 6794-[4-chloro-2-(1H-pyrazol-4-yl)phenoxy]-2,5- 469 [M³⁵ClH]+difluoro-N-1,3-thiazol-2-ylbenzenesulfonamide 6804-[4-chloro-2-(1H-pyrazol-4-yl)phenoxy]-2- 451 [M³⁵ClH]+fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide 6814-[4-chloro-2-(1-methyl-1H-pyrazol-5- 465 [M³⁵ClH]+yl)phenoxy]-2-fluoro-N-1,3-thiazol-4- ylbenzenesulfonamide 6822,5-difluoro-N-(5-fluoro-1,3-thiazol-2-yl)-4-{4- 535 [MH]+[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}benzenesulfonamide 6834-[4-chloro-2-(1H-pyrazol-4-yl)phenoxy]-2,5- 487 [M³⁵ClH]+difluoro-N-(5-fluoro-1,3-thiazol-2- yl)benzenesulfonamide 6843-fluoro-4-{4-[1-methyl-3-(trifluoromethyl)-1H- 499 [MH]+pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 6854-[4-chloro-2-(1H-pyrazol-4-yl)phenoxy]-3- 451 [M³⁵ClH]+fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide 6863-fluoro-4-[4-fluoro-2-(1H-pyrazol-4- 435 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 6873-fluoro-4-[2-(1H-pyrazol-4-yl)-4- 501 [MH]+(trifluoromethoxy)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 6885-Chloro-2-fluoro-4-[4-fluoro-2-(3-methoxy-1- 513 [M³⁵ClH]+methyl-1H-pyrazol-5-yl)-phenoxy]-N-1,3- thiazol-4-yl-benzenesulfonamide689 5-Chloro-2-fluoro-4-{2-[5- 560 [M³⁵ClH]+(hydroxymethyl)pyridin-3-yl]-4-(trifluoromethyl)phenoxy}-N-1,3-thiazol-4- ylbenzenesulfonamide 6904-(2-azetidin-3-yl-4-chlorophenoxy)-3-cyano-N- 447 [M³⁵ClH]+1,3-thiazol-2-ylbenzenesulfonamide 6914-{4-chloro-2-[3-(trifluoromethyl)-1H-pyrazol-4- 524 [M³⁵ClH]−yl]phenoxy}-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 6924-[(5-chloro-2′-methylbiphenyl-2-yl)oxy]-3- 482 [M³⁵ClH]+cyano-N-1,3-thiazol-2-ylbenzenesulfonamide 6934-[4-chloro-2-(1-methyl-1H-pyrazol-4- 472 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 6944-[4-chloro-2-(1H-1,2,3-triazol-5-yl)phenoxy]-3- 459 [M³⁵ClH]+cyano-N-1,3-thiazol-2-ylbenzenesulfonamide 6954-{4-[4-chloro-1-ethyl-3-(trifluoromethyl)-1H- 554 [M³⁵ClH]+pyrazol-5-yl]phenoxy}-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 6963-cyano-4-[4-iodo-2-(1H-pyrazol-4-yl)phenoxy]- 550 [MH]+N-1,3-thiazol-2-ylbenzenesulfonamide 6974-[4-Bromo-2-(1H-pyrazol-4-yl)phenoxy]-3- 502 [M⁷⁹BrH]+cyano-N-1,3-thiazol-2-ylbenzenesulfonamide 6984-[4-chloro-2-(4-methyl-1,3-thiazol-5- 489 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 6993-cyano-4-[2-(1-methyl-1H-pyrazol-5-yl)-5- 506 [MH]+(trifluoromethyl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 7004-(4-chloro-2-pyridin-3-ylphenoxy)-3-cyano-N- 469 [M³⁵ClH]+1,3-thiazol-2-ylbenzenesulfonamide 7014-(4-chloro-2-pyrimidin-5-ylphenoxy)-3-cyano- 470 [M³⁵ClH]+N-1,3-thiazol-2-ylbenzenesulfonamide 7023-cyano-4-[4-fluoro-2-(6-fluoropyridin-3- 469 [MH]−yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 7033-cyano-4-[(4′-cyano-3′-methoxybiphenyl-2- 489 [MH]+yl)oxy]-N-1,3-thiazol-2-ylbenzenesulfonamide 7043-cyano-4-[2-(1H-pyrazol-4-yl)-4- 508 [MH]+(trifluoromethoxy)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 7054-[4-bromo-2-(1-methyl-1H-pyrazol-5- 516 [M⁷⁹BrH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 7064-[2-(3-amino-1H-pyrazol-4-yl)-4- 473 [M³⁵ClH]+chlorophenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 7074-[2-(5-amino-1H-pyrazol-4-yl)phenoxy]-3- 439 [MH]+cyano-N-1,3-thiazol-2-ylbenzenesulfonamide 7083-cyano-4-{4-[3-(difluoromethyl)-5- 504 [MH]+(hydroxymethyl)-1H-pyrazol-1-yl]phenoxy}-N-1,3-thiazol-2-ylbenzenesulfonamide 7094-[4-chloro-2-(1H-pyrazol-5-yl)phenoxy]-3- 458 [M³⁵ClH]+cyano-N-1,3-thiazol-2-ylbenzenesulfonamide 7104-[4-chloro-2-(4-fluoro-1H-pyrazol-5- 476 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-2- ylbenzenesulfonamide 7114-[5-chloro-2-(1H-pyrazol-5-yl)phenoxy]-3- 458 [M³⁵ClH]+cyano-N-1,3-thiazol-2-ylbenzenesulfonamide 7124-(biphenyl-2-yloxy)-3-cyano-N-(5-fluoro-4- 466 [MH]+methyl-1,3-thiazol-2-yl)benzenesulfonamide 7133-Cyano-N-(5-fluoro-1,3-thiazol-2-yl)-4-[4-iodo- 568 [MH]+2-(1H-pyrazol-5-yl)phenoxy]benzenesulfonamide 7143-cyano-N-(5-fluoro-1,3-thiazol-2-yl)-4-[4-(3- 500 [MH]+hydroxypropyl)-2-(1H-pyrazol-4- yl)phenoxy]benzenesulfonamide 7153-cyano-N-(5-fluoro-1,3-thiazol-2-yl)-4-[4-(3- 514 [MH]+hydroxypropyl)-2-(1-methyl-1H-pyrazol-5- yl)phenoxy]benzenesulfonamide716 3-cyano-N-(5-fluoro-1,3-thiazol-2-yl)-4-[4-(2- 500 [MH]+hydroxyethyl)-2-(1-methyl-1H-pyrazol-5- yl)phenoxy]benzenesulfonamide717 4-[4-chloro-2-(1-methyl-1H-1,2,4-triazol-5- 491 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-(5-fluoro-1,3-thiazol-2- yl)benzenesulfonamide 7183-cyano-N-(5-fluoro-1,3-thiazol-2-yl)-4-[2-(1- 524 [MH]+methyl-1H-pyrazol-5-yl)-4- (trifluoromethyl)phenoxy]benzenesulfonamide719 3-cyano-4-{3-fluoro-4-[1-methyl-3- 542 [MH]+(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide 7204-{2-chloro-4-[1-methyl-3-(trifluoromethyl)-1H- 558 [M³⁵ClH]+pyrazol-5-yl]phenoxy}-3-cyano-N-(5-fluoro-1,3-thiazol-2-yl)benzenesulfonamide 721 4-[4-Cyano-2-(1-methyl-1H-pyrazol-5-456 [MH]+ yl)phenoxy]-3-fluoro-N-1,3-thiazol-2- ylbenzenesulfonamide 7224-[5-Chloro-2-(1H-pyrazol-5-yl)phenoxy]-3- 451 [M³⁵ClH]+fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide 7233-Fluoro-4-[4-isobutyl-2-(1-methyl-1H-pyrazol- 487 [MH]+5-yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 7243-chloro-4-[4-chloro-2-(1H-pyrazol-4- 468 [M³⁵ClH]+yl)phenoxy]-N-1,2,4-thiadiazol-5- 470 [M³⁷ClH]+ ylbenzenesulfonamide 7254-{4-chloro-2-[1-(1-methylpiperidin-4-yl)-1H- 556 [M³⁵ClH]+pyrazol-5-yl]phenoxy}-3-cyano-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide726 4-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4- 540 [M³⁵ClH]+chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol- 4-ylbenzenesulfonamide727 4-[2-(1-azetidin-3-yl-1H-pyrazol-4-yl)-4- 547 [MH]+(trifluoromethyl)phenoxy]-3-cyano-N-1,3- thiazol-4-ylbenzenesulfonamide728 4-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4- 514 [M³⁵ClH]+chlorophenoxy]-3-cyano-N-1,2,4-thiadiazol-5- 516 [M³⁷ClH]+ylbenzenesulfonamide 729 4-{4-chloro-2-[1-(1-methylazetidin-3-yl)-1H-527 [M³⁵ClH]+ pyrazol-5-yl]phenoxy}-3-cyano-N-1,3-thiazol-4-ylbenzenesulfonamide 730 5-chloro-4-{4-chloro-2-[1-(1-methylazetidin-3-554 [M³⁵ClH]+ yl)-1H-pyrazol-5-yl]phenoxy}-2-fluoro-N-1,3- 556 [M³⁷ClH]+thiazol-4-ylbenzenesulfonamide 7314-{4-chloro-2-[1-(1-methylazetidin-3-yl)-1H- 538 [M³⁵ClH]+pyrazol-5-yl]phenoxy}-2,5-difluoro-N-1,3- thiazol-4-ylbenzenesulfonamide732 4-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-5- 512 [M³⁵ClIH]+chloro-2-fluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 7332,5-difluoro-4-[2-(1,2,3,6-tetrahydropyridin-4- 519 [MH]+yl)-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 7344-[4-chloro-2-(1-methylpiperidin-4-yl)phenoxy]- 501 [M³⁵ClH]+2,5-difluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 7352-[4-bromo-2-(1-methyl-1H-pyrazol-5- 535 [M⁷⁹BrH]+yl)phenoxy]-5-[(1,2,4-thiadiazol-5- 537 [M⁸¹BrH]+ylamino)sulfonyl]benzamide 736 4-[4-chloro-2-(2-piperazin-1-ylpyridin-4-554 [MH]+ yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide737 4-[4-chloro-2-(1H-pyrazol-4-yl)phenoxy]-3- 452 [M³⁵ClH]+fluoro-N-1,2,4-thiadiazol-5- 454 [M³⁷ClH]+ ylbenzenesulfonamide 450[M³⁵ClH]− 452 [M³⁷ClH]− 738 4-[4-chloro-2-(1H-pyrazol-4-yl)phenoxy]-2,5-470 [M³⁵ClH]+ difluoro-N-1,2,4-thiadiazol-5- 472 [M³⁷ClH]+ylbenzenesulfonamide 468 [M³⁵ClH]− 470 [M³⁷ClH]− 7396-[4-chloro-2-(1-methyl-1H-pyrazol-5- 473 [MH]+yl)phenoxy]-5-cyano-N-1,3-azol-2-ylpyridine-3- 471 [MH]− sulfonamide 7405-cyano-6-{4-[1-ethyl-3-(trifluoromethyl)-1H- 521 [MH]+pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2- 519 [MH]−ylpyridine-3-sulfonamide 741 3-cyano-4-[2-(1H-pyrazol-5-yl)-4- 493 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5- 491 [MH]−ylbenzenesulfonamide 742 4-[2-(3-amino-1H-pyrazol-4-yl)-4- 485 [M³⁵ClH]+chlorophenoxy]-2,5-difluoro-N-1,2,4-thiadiazol- 487 [M³⁷ClH]+5-ylbenzenesulfonamide 7434-[4-chloro-2-(2-chloropyridin-4-yl)phenoxy]-3- 504 [M³⁵ClH]+cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 7443-chloro-4-(4-chloro-2-piperidin-4-ylphenoxy)- 479 [M³⁵ClH]+N-pyrimidin-4-ylbenzenesulfonamide 7453-chloro-4-[4-chloro-2-(1-methyl-1H-pyrazol-5- 493 [M³⁵ClH]+yl)phenoxy]-N-(5-fluoropyridin-2- yl)benzenesulfonamide 7463-chloro-4-[4-chloro-2-(1H-pyrazol-5- 462 [M³⁵ClH]+yl)phenoxy]-N-pyrimidin-4- ylbenzenesulfonamide 7473-chloro-4-[4-chloro-2-(1H-pyrazol-5- 468 [M³⁵ClH]+yl)phenoxy]-N-1,3,4-adiazol-2- ylbenzenesulfonamide 7485-chloro-4-{4-chloro-2-[1-(2-hydroxyethyl)-1H- 530 [M³⁵ClH]+pyrazol-5-yl]phenoxy}-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide 7494-[4-chloro-2-(3-methyl-1H-pyrazol-4- 465 [M³⁵ClH]+yl)phenoxy]-3-fluoro-N-1,3-thiazol-2- ylbenzenesulfonamide 7502,5-difluoro-4-[2-(1H-pyrazol-4-yl)-4- 519 [M³⁵ClH]+(trifluoromethoxy)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 7514-[5-chloro-4-fluoro-2-(1H-pyrazol-5- 477 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 7524-[5-chloro-4-fluoro-2-(1H-pyrazol-4- 488 [M³⁵ClH]+yl)phenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 7534-[5-chloro-4-fluoro-2-(1H-pyrazol-5- 488 [M³⁵ClH]+yl)phenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 7544-[5-chloro-4-fluoro-2-(1H-pyrazol-4- 477 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 7555-chloro-2-fluoro-4-[4-fluoro-2-(1H-pyrazol-4- 470 [M³⁵ClH]+yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 7562,5-difluoro-4-[4-fluoro-2-(1H-pyrazol-4- 454 [MH]+yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 7574-[4-chloro-5-fluoro-2-(1H-pyrazol-4- 488 [M³⁵ClH]+yl)phenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 7585-chloro-6-{4-[1-ethyl-3-(trifluoromethyl)-1H- 530 [M³⁵ClH]+pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2- ylpyridine-3-sulfonamide 7595-chloro-6-[4-chloro-2-(1-methyl-1H-pyrazol-5- 482 [M³⁵ClH]+yl)phenoxy]-N-1,3-thiazol-2-ylpyridine-3- sulfonamide 7604-[4-chloro-2-(1-piperidin-4-yl-1H-pyrazol-5- 541 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-4- ylbenzenesulfonamide 7614-[4-chloro-2-(1-piperidin-4-yl-1H-pyrazol-3- 541 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-4- ylbenzenesulfonamide 7624-[4-chloro-5-fluoro-2-(1H-pyrazol-5- 488 [M³⁵ClH]+yl)phenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 7634-[4-chloro-5-fluoro-2-(1H-pyrazol-5- 477 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 7645-chloro-2-fluoro-4-[2-(1H-pyrazol-4-yl)-4- 520 [M³⁵ClH]+(trifluoromethyl)phenoxy]-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 7655-chloro-4-(4-chloro-2-piperidin-4-ylphenoxy)-2- 503 [M³⁵ClH]+fluoro-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 7664-[2-(6-aminopyridin-2-yl)-4-chlorophenoxy]-3- 484 [M³⁵ClH]+cyano-N-1,3-thiazol-4-ylbenzenesulfonamide 7674-[4-chloro-2-(1H-pyrazol-4-yl)phenoxy]-3- 458 [M³⁵ClH]+cyano-N-1,3-thiazol-4-ylbenzenesulfonamide 7683-cyano-4-[3-(1H-pyrazol-3-ylmethyl)phenoxy]- 438 [MH]+N-1,3-thiazol-4-ylbenzenesulfonamide 7694-{3-[(1-tert-butyl-1H-pyrazol-3- 494 [MH]+yl)methyl]phenoxy}-3-cyano-N-1,3-thiazol-4- ylbenzenesulfonamide 7704-(biphenyl-2-yloxy)-3-cyano-N-[5- 496 [MH]+ (trifluoromethyl)pyridin-2-yl]benzenesulfonamide 771N-(5-chloro-1,3-thiazol-2-yl)-4-[4-cyano-2-(1H- 494 [M³⁵ClH]+pyrazol-4-yl)phenoxy]-2,5- difluorobenzenesulfonamide 7724-[4-chloro-2-(1-methyl-1H-pyrazol-5- 534 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-[5-(trifluoro-methyl)pyridin-2-yl]benzenesulfonamide 7735-chloro-2-fluoro-4-[5-fluoro-2-(1H-pyrazol-5- 470 [M³⁵ClH]+yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 7743-cyano-4-[4-(4-fluoro-1H-pyrazol-1- 442 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 7754-[2-(1-tert-butyl-1H-pyrazol-5-yl)-4- 515 [M³⁵ClH]+chlorophenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 7764-[4-chloro-2-(1-methyl-1H-pyrazol-5- 480 [M³⁵ClH]+yl)phenoxy]-3-fluoro-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide 7775-chloro-4-[4-chloro-2-(1H-1,2,3-triazol-5- 486 [M³⁵ClH]+yl)phenoxy]-2-fluoro-N--thiazol-4- ylbenzenesulfonamide 7784-(biphenyl-3-yloxy)-3-cyano-N-1,3-thiazol-2- 434 [MH]+ylbenzenesulfonamide 779 3-cyano-4-{2-fluoro-5-[1-methyl-3- 524 [MH]+(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-N-1,3-thiazol-2-ylbenzenesulfonamide 7803-cyano-N-(5-fluoro-1,3-thiazol-2-yl)-4-[5-iodo- 582 [MH]+2-(1-methyl-1H-pyrazol-5- yl)phenoxy]benzenesulfonamide 7812,5-difluoro-4-[4-fluoro-2-(1H-pyrazol-5- 454 [MH]+yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide

Example 5874-[2-(6-Aminopyridin-3-yl)-4-fluorophenoxy]-N-(5-chloro-1,3-thiazol-2-yl)-3-cyanobenzenesulfonamide

Example 587 from above can be prepared as follows.

N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-N-(2,4-dimethoxybenzyl)-4-(4-fluoro-2-iodophenoxy)benzenesulfonamide(Preparation 217, 100 mg, 0.146 mmol), 2-aminopyridine-5-boronic acidpinacol ester (35.4 mg, 0.161 mmol), palladium (0)tetrakis(triphenylphoshine) (17.3 mg, 0.015 mmol) and caesium carbonate(143 mg, 0.438 mmol) were charged to a 25 ml round-bottomed flask andpurged with nitrogen (×3). To this was added fresh degassed 1,4-dioxane(4 ml) and fresh degassed water (1 ml) and the vessel was heated to 60°C. and stirred for 16 hours. The solvent was removed in vacuo and theresidue was dissolved in methanol (2 ml) before loading on to a ISOLUTE™SCX-2 cartridge (2 g). The cartridge was washed with methanol (50 ml)followed by ammonia (2 M in methanol, 50 ml). The basic washes wereconcentrated in vacuo and the residue was dissolved in dichloromethane(10 ml). To this solution was added trifluoroacetic acid (1 ml) and thesolution stirred at room temperature for 18 hours before concentratingin vacuo. The residue was dissolved in methanol (2 ml) and loaded on toa ISOLUTE™ PE-AX cartridge (5 g). The cartridge was washed with methanol(3 column volumes) followed by formic acid (2% solution in methanol, 3column volumes). The acidic washes were concentrated in vacuo to afforda sticky yellow solid which was triturated in dichloromethane to affordthe title compound as a white solid.

Yield 28 mg, 38%.

LCMS R_(t)=2.04 minutes. MS m/z 502 [M³⁵ClH]+

¹HNMR (d₆-DMSO): δ 6.35 (b s, 2H), 6.45 (m, 1H), 6.75 (m, 1H), 7.32 (m,1H), 7.48 (m, 3H), 7.55 (m, 1H), 7.9 (m, 1H), 8.0 (m, 1H), 8.1 (m, 1H).

Example 6555-chloro-4-(4-chloro-2-piperidin-4-ylphenoxy)-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide

Example 655 from above can be made as follows. To a solution oftert-butyl 4-(5-chloro-2-hydroxyphenyl)piperidine-1-carboxylate(Preparation 231, 38 mg, 0.122 mmol) and potassium carbonate (50.6 mg,0.366 mmol) in dimethyl sulfoxide (1 mL) was added tert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate(Preparation 453, 50 mg, 0.122 mmol). The mixture was stirred at roomtemperature for 16 hours before diluting with ethyl acetate (10 mL) andwater (10 mL). The aqueous phase was acidified to pH 4 with saturatedcitric acid solution (aqueous) and extracted with ethyl acetate (3×10mL). The combined organic layers were washed with saturated aqueoussodium chloride solution (30 mL), dried over sodium sulphate, filteredand concentrated in vacuo to afford tert-butyl4-[2-(4-{[(tert-butoxycarbonyl)(1,3-thiazol-4-yl)amino]sulfonyl}-2-chloro-5-fluorophenoxy)-5-chlorophenyl]piperidine-1-carboxylateas a white foam. This was dissolved in dichloromethane (1 mL),trifluoroacetic acid added (200 μL) and reaction stirred for 16 hours atroom temperature before concentrating in vacuo. Purification bypreparative HPLC afforded the title compound.

LCMS Rt=1.05 minutes. MS m/z 502 [M³⁵ClH]+

Example 7824-[4-Chloro-2-(1H-pyrazol-4-yl)phenoxy]-3-cyano-N-1,3-thiazol-2-ylbenzenesulfonamide

tert-Butyl 4-(5-chloro-2-hydroxyphenyl)-1H-pyrazole-1-carboxylate(Preparation 205, 624 mg, 2.12 mmol),3-cyano-4-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide (Preparation 46,500 mg, 1.76 mmol) and potassium carbonate (732 mg, 5.30 mmol) werestirred in dimethyl sulphoxide (10 ml) at 50° C. for 2 hours. Thereaction was cooled to room temperature and the mixture poured dropwiseinto hydrochloric acid (2M aqueous, 100 ml). The mixture was stirred atroom temperature for 18 hours. The precipitate was filtered andsuspended in methanol (10 ml). The mixture was treated with hydrogenchloride (4M in dioxane, 2 ml). The mixture was then stirred at roomtemperature over for 60 hours. The mixture was evaporated in vacuo. Theresidue was dissolved in methanol (5 ml). The black solution was passedthrough an ISOLUTE™ SCX cartridge. The cartridge was eluted withmethanol (100 ml) followed by ammonia (2M in methanol). The dark ammoniasolution was evaporated in vacuo. The residue was dissolved indichloromethane/methanol (95/5, 5 ml) and passed through a pad ofsilica. The solution was evaporated in vacuo. The residue was purifiedusing a silica gel column chromatography eluting withdichloromethane:ethyl acetate (gradient 1:0 to 1:9, by volume).Concentration in vacuo afforded the title compound as a white solid.Yield 427 mg, 53%

LCMS Rt=2.26 minutes, MS m/z 458 [M³⁵ClH]+

¹HNMR (d₆-DMSO): δ 6.87 (m, 2H), 7.28 (d, 1H), 7.32-7.41 (m, 3H), 7.87(m, 3H), 8.12 (br. s, 1H), 8.23 (d, 1H), 12.83 (br. s, 1H), 13.08 (br.s, 1H).

Example 7833-cyano-4-[2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethoxy)phenoxy]-N-1,3-thiazol-2-ylbenzenesulfonamide

2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethoxy)phenol (Preparation533, 50.0 mg, 0.20 mmol) and3-cyano-4-fluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide (Preparation 46,57 mg, 0.20 mmol) were used to prepare the title compound using Method Fabove. The product was purified by flash column chromatography (SiO₂)eluting with dichloromethane:ethyl acetate (gradient 8:2 to 2:8, byvolume) to afford the title compound, 98 mg, 97% yield.

LCMS Rt=1.47 minutes. MS m/z 522 [MH]+

¹H NMR (400 MHz, CDCl₃): δ 3.86 (s, 3H), 6.21 (d, 1H), 6.58 (d, 1H),6.66 (d, 1H), 7.10 (d, 1H), 7.24 (d, 1H), 7.33 (d, 1H), 7.36-7.42 (m,2H), 7.91 (dd, 1H), 8.09 (d, 1H), 11.64 (br. s, 1H) ppm.

¹⁹F NMR (376 MHz, CDCl₃): δ −58.52 (s) ppm.

Example 7844-(2-azetidin-3-yl-4-chlorophenoxy)-5-chloro-N-(5-chloro-1,3-thiazol-2-yl)-2-fluorobenzenesulfonamide

5-Chloro-N-(5-chloro-1,3-thiazol-2-yl)-N-(2,4-dimethoxybenzyl)-2,4-difluorobenzenesulfonamide(Preparation 655) and tert-butyl3-(5-chloro-2-hydroxyphenyl)azetidine-1-carboxylate (Preparation 237)were stirred in dichloromethane (2 ml) and trifluoroacetic acid (1 ml)to prepare the title compound using Method F above but where theN,N-dimethylformamide was replaced with dimethyl sulphoxide. The crudeproduct was concentrated in vacuo and purified by preparative HPLC toafford the title compound.

LCMS Rt=2.47 minutes MS m/z 509 [M³⁵ClH]+

Example 785N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-[4-fluoro-2-(1H-pyrazol-4-yl)phenoxy]benzenesulfonamide

N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-(4-fluoro-2-iodophenoxy)benzenesulfonamide(Preparation 240, 50 mg, 0.09 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (27 mg, 0.14mmol) palladium (0) tetrakis(triphenylphosphine) (10 mg, 0.009 mmol) andsodium carbonate (30 mg, 0.28 mmol) were dissolved indimethylformamide:water (2:1, 1.5 ml) and heated to 90° C. for 18 hours.The reaction was partitioned between ethyl acetate and saturated aqueoussodium chloride solution. The organic layer was separated, dried oversodium sulfate and evaporated in vacuo to afford a brown oil.Purification by preparative HPLC afforded the title compound. Yield 12.5mg 30%.

LCMS=Rt2.50 minutes. MS m/z 476 [M³⁵ClH]+

Example 786N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-[4-chloro-2-(1H-pyrazol-4-yl)phenoxy]benzenesulfonamide

The title compound was prepared according to the same method as thatused for Example 785 above using4-(4-chloro-2-iodophenoxy)-N-(5-chloro-1,3-thiazol-2-yl)-3-cyanobenzenesulfonamide(Preparation 219) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as startingmaterials. Purification by preparative HPLC afforded the title compound.Yield 7.8 mg 17%.

LCMS=Rt 2.45 minutes. MS m/z 492 [M³⁵ClH]+

¹HNMR (400 MHz, CDCl₃): δ 6.63 (d, 1H), 6.8 (s, 1H), 7.05 (d, 1H), 7.22(m, 1H), 7.60 (s, 1H), 7.80 (m, 3H), 8.15 (s, 1H)

Example 7874-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

A suspension ofN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 647, 10 g, 22.45 mmol),2-(2-aminopyridin-4-yl)-4-chlorophenol (Preparation 258, 5 g, 22.67mmol) and potassium carbonate (3.72 g, 26.94 mmol) in dimethyl sulfoxide(150 mL) was stirred at room temperature for 2 hours. The reaction waspartitioned between ethyl acetate (150 mL) and saturated aqueous sodiumchloride solution (150 mL). The organic layer was collected andconcentrated in vacuo to afford an orange residue. This was dissolved indichloromethane (145 mL) and trifluoroacetic acid (8.48 mL) was added.The reaction was stirred at room temperature for 24 hours beforeconcentrating in vacuo to afford a pink residue. This was taken up inethyl acetate (200 mL) to form a white slurry that was washed withsaturated sodium bicarbonate solution (200 mL). Filtration yielded awhite solid that was dried in vacuo, slurried in water and hydrochloricacid (1 N aqueous solution, 1.05 eq) and extracted with ethyl acetate.The organic layer was collected and concentrated in vacuo to yield thetitle compound.

LCMS Rt=1.92 minutes. MS m/z 496 [M³⁵ClH]+

1H NMR (d₆-DMSO): δ 6.95 (m, 1H), 7.05 (s, 1H), 7.20-7.30 (m, 2H), 7.55(d, 1H), 7.65 (s, 1H), 7.75 (m, 1H), 7.95-8.05 (m, 3H), 8.40 (s, 1H).

Example 7884-[2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide

To a suspension of sodium hydride (29 mg, 1.2 mmol) in dimethylformamide(1 mL) was addedN-(1-tert-butyl-4-(5-chloro-2-hydroxyphenyl)-1H-pyrazol-5-yl)-2,2,2-trifluoroacetamide(Preparation 209, 239 mg, 0.661 mmol) and stirred for 30 minutes. Tothis was added tert-butyl5-chloro-2,4-difluorophenylsulfonyl(thiazol-4-yl)carbamate (Preparation453, 206 mg, 0.501 mmol) and stirred for 24 hours. After this time onlya small amount of product was observed, so potassium carbonate (40 mg,0.3 mmol) was added and the reaction heated at 55° C. for 3 days. Thereaction was cooled, diluted with ethyl acetate and the organic extractwashed with water and saturated aqueous sodium chloride solution, driedover magnesium sulfate, filtered and concentrated in vacuo. Purificationby automated flash column chromatography eluting with ethylacetate:hexanes (gradient 0:1 to 1:0, by volume) afforded fullyprotected product. This residue was dissolved in methanol (1 mL) andsodium carbonate solution (2 M aqueous, 0.08 mL, 0.2 mmol) and water(0.2 mL) added. The reaction was stirred at room temperature for 6 hoursand then heated at 55° C. for 16 hours before concentrating in vacuo andpassing through a short silica gel column eluting withmethanol:dichloromethane (gradient 0:1 to 1:9, by volume). All productrelated fractions were combined, concentrated in vacuo, dissolved inmethanol (saturated in gaseous hydrogen chloride) and heated at 50° C.for 16 hours. Purification by preparative HPLC afforded the titlecompound as a white solid, 31 mg, 12% yield.

LCMS Rt=1.72 minutes. MS m/z 500 [M³⁵ClH]+

¹H NMR (300 MHz, d₆-DMSO): δ 6.85 (d, 1H), 7.11 (m, 1H), 7.24 (m, 1H),7.41 (dd, 1H), 7.71 (m, 2H), 7.93 (d, 1H), 8.93 (m, 1H), 11.45 (br s,1H).

Example 7892,5-difluoro-4-[2-(1H-pyrazol-5-yl)-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

A suspension ofN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-[2-iodo-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 363, 100 mg, 0.14 mmol), potassium carbonate (48 mg, 1.12mmol) and1-(ethoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Preparation 337, 70 mg, 0.28 mmol) in 1,4-dioxane (5 mL) and water (2mL) was degassed and palladium tetrakis (16 mg, 0.014 mmol) added beforeheating at 80° C. for 16 hours. Dicholoromethane (20 mL) and water (10mL) were added and the organics separated and evaporated in vacuo toafford the crude product. Dicholoromethane (10 mL) and trifluoroaceticacid (5 mL) were added and the reaction mixture was stirred at roomtemperature for 16 hours before concentrating in vacuo. Hydrochloricacid (4 M in 1,4-dioxane, 10 mL) was added and the reaction mixture wasstirred for 16 hours before concentrating in vacuo. The residue waspurified by reverse phase chromatography to afford the desired product,6 mg, 9% yield.

LCMS Rt=4.23 minutes. MS m/z 504 [MH]+

¹H NMR (CD₃OD): δ 8.05 (m, 1H), 8.30 (m, 1H), 8.70 (m, 1H), 8.95-9.10(m, 3H), 9.70 (m, 2H).

Example 7902,5-difluoro-4-[2-(1H-pyrazol-4-yl)-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

The title compound was prepared according to the same method as thatused for Example 789 above usingN-(2,4-dimethoxybenzyl)-2,5-difluoro-4-[2-iodo-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 363) and the boronic ester tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.Purificiation using reverse phase chromatography afforded the titlecompound.

LCMS Rt=3.98 minutes. MS m/z 504 [MH]+

¹H NMR (CD₃OD): δ 8.30 (m, 1H), 8.60 (m, 1H), 8.85 (m, 1H), 9.05 (m,1H), 9.35-9.45 (m, 3H), 10.65 (s, 1H).

Example 7914-(4-chloro-2-(1H-pyrazol-4-yl)phenoxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

The title compound was prepared from4-(4-chloro-2-iodophenoxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(Preparation 355) and(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole using Method Eabove with microwave irradiation for 1 hour at 85° C.

LCMS Rt=3.24 minutes MS m/z 457 [M³⁵ClH]−

¹HNMR (400 MHz, d₆-DMSO): δ 6.85 (d, 1H), 7.30-7.40 (m, 2H), 7.95 (m,2H), 8.00 (s, 2H), 8.25 (s, 1H), 8.45 (s, 1H)

Example 7924-[2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

To a solution of theN-{1-tert-butyl-4-[5-chloro-2-(2-cyano-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}phenoxy)phenyl]-1H-pyrazol-5-yl}-2,2,2-trifluoroacetamide(Preparation 419, 157 mg, 0.20 mmol) in methanol (15 ml) was addedhydrogen chloride (4 M in 1,4-dioxane, 3 ml). The resulting yellowsolution was stirred and heated at 60° C. for 48 hours. The solventremoved in vacuo to afford a pale yellow residue. The material waspurified by column chromatography (80 g silica gel column) eluting withmethanol:dichloromethane (5:95, by volume) to afford the title compoundas a yellow oily solid, 56 mg, 59% yield.

LCMS Rt=3.09 minutes. MS m/z 474 [M³⁵ClH]+

¹H NMR (CD₃OD): δ 6.64-6.70 (m, 1H), 7.19-7.22 (m, 1H), 7.31-7.38 (m,1H), 7.50 (br-s, 1H), 7.64 (br-s, 1H), 7.86-7.90 (m, 2H), 8.10 (s, 1H).

Example 7933-cyano-4-[2-(1H-pyrazol-5-yl)-4-(trifluoromethoxy)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

3-cyano-N-(1,2,4-thiadiazol-5-yl)-4-[2-iodo-4-(trifluoromethoxy)phenoxy]benzenesulfonamide(Preparation 760, 500 mg, 0.88 mmol),1-(ethoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Preparation 337, 600 mg, 1.4 mmol), palladium (0) tetrakistriphenylphosphine (78 mg, 0.067 mmol) and sodium carbonate (420 mg,3.963 mmol) were dissolved in a mixture of water (4 mL) and 1,4-dioxane(12 mL) and heated to 85° C. under N₂ for 7 hours. Further1-(ethoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(100 mg 0.23 mmol) and palladium (0) tetrakis triphenylphosphine (10 mg,0.008 mmol) were added and the reaction stirred at 85° C. under N₂ for18 hours. The reaction was quenched by the addition of ethyl acetate (20mL) and saturated aqueous brine solution (20 mL). The organic layer wascollected, dried over sodium sulphate and concentrated in vacuo beforepurification using silica gel column chromatography (v/v/vdichloromethane:methanol:acetic acid v/v/v 100:0:0 to 95:5:0.5) toafford a white solid. This was dissolved in 4M HCl in 1,4-dioxane (5 mL)and stirred at room temperature for 4 hours before concentration invacuo and purification using silica gel column chromatography (v/v/vdichloromethane:methanol:acetic acid 100:0:0 to 90:10:1 to afford aresidue that was triturated in dichloromethane (5 mL) to afford 210 mgof the title compound as a white solid as the HCl salt.

LCMS Rt=1.56 minutes. MS m/z 509 [MH]+

¹H NMR (d₆-DMSO): δ 6.55 (s, 1H), 6.85 (d, 1H), 7.45-7.50 (m, 2H), 7.75(s, 1H), 7.90-8.00 (m, 2H), 8.25 (s, 1H), 8.45 (s, 1H)

Example 7944-[2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

Dimethyl sulfoxide (5.0 mL) was added to a flask containingN-[1-tert-butyl-4-(5-chloro-2-hydroxyphenyl)-1H-pyrazol-5-yl]-2,2,2-trifluoroacetamide(Preparation 209, 0.100 g, 0.000276 mol),5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 333, 0.116 g, 0.000251 mol) and potassium carbonate (0.104g, 0.000753 mol) and the reaction mixture was stirred at roomtemperature under nitrogen for 16 hours. The reaction mixture was pouredinto water (50.0 mL) and the aqueous extracted with ethyl acetate(4×30.0 mL). The combined organics were washed with saturated aqueoussodium chloride solution (30 mL), dried over magnesium sulfate, filteredand concentrated in vacuo. The residue was dissolved in methanol (5.0mL) and hydrochloric acid (4 M in 1,4-dioxane, 5.0 mL, 0.020 mol) andstirred at 100° C. under nitrogen for 16 hours. The mixture wasconcentrated in vacuo and the residue was purified by reverse phasechromatography eluting with water:acetonitrile:trifluoroacetic acid(gradient 95:5:0.1 to 30:70:0.1, by volume) to afford a colourless gum.This was triturated with heptane to afford the title compound as a whitepowder, 0.030 g, 22% yield.

LCMS R_(t)=3.40 minutes. MS m/z 501 [M³⁵Cl³⁵ClH]+

¹H NMR (400 MHz, d₆-DMSO): δ 6.75 (m, 1H), 7.2 (m, 1H), 7.35 (m, 1H),7.55 (s, 1H), 7.65 (m, 1H), 7.85 (m, 1H), 8.4 (s, 1H).

Example 7953-cyano-4-[2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethoxy)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

The title compound was prepared from3-cyano-N-(2,4-dimethoxybenzyl)-4-[2-iodo-4-(trifluoromethoxy)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 497) and 1-methyl-1H-pyrazole-5-boronic acid pinacol esterusing Method E above. Purification afforded the title compound.

LCMS R_(t)=3.96 minutes. MS m/z 523 [MH]+

¹H NMR (CDCl₃): δ 3.9 (s, 3H), 6.25 (m, 1H), 6.7 (m, 1H), 7.3-7.45 (m,3H), 7.9 (m, 1H), 8.05 (m, 3H).

Example 7965-chloro-4-(4-chloro-2-piperidin-4-ylphenoxy)-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

To a solution of tert-butyl4-(5-chloro-2-hydroxyphenyl)piperidine-1-carboxylate (Preparation 231,0.500 g, 0.0014 mol) and potassium carbonate (0.579 g, 0.00419 mol) indimethyl sulfoxide (5.0 mL) was added5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 333, 0.644 g, 0.0014 mol). The mixture was stirred at roomtemperature under nitrogen for 1.5 hours before diluting with ethylacetate (10.0 mL) and water (10.0 mL). The aqueous layer was extractedwith ethyl acetate (3×10.0 mL). The combined organic extracts werewashed with saturated aqueous sodium chloride solution (30 mL), driedover sodium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography (40 g silica gel column) eluting withethyl acetate:heptane (gradient 0:1 to 35:65, by volume) to afford 1.03g of tert-butyl4-[5-chloro-2-(2-chloro-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}-5-fluorophenoxy)phenyl]piperidine-1-carboxylateas a white solid. This material was dissolved in dichloromethane (5.0mL), trifluoroacetic acid (1.0 mL) added and reaction stirred for 16hours at room temperature under nitrogen. Methanol (5.0 mL) was added toafford a white precipitate. This suspension mixture was filtered througha Celite™ pad and washed with methanol. The filtrate was concentrated invacuo and the residue was diluted with methanol (2.0 mL),dichloromethane (2.0 mL) and saturated aqueous sodium bicarbonate (4.0mL) and stirred for 1 hour at room temperature to afford a white solid.The suspension was filtered and the solid washed with water and diethylether. The collected solid was recrystallised from hot acetonitrile andethanol (1:1 v/v) to afford the title compound as a white solid, 0.1929mg, 27% yield.

¹HNMR (400 MHz, d₆-DMSO): δ 1.83 (m, 2H), 1.95 (m, 2H), 3.02 (m, 3H),3.33 (d, 2H), 6.90 (d, 1H), 7.00 (dd, 1H), 7.33 (m, 2H), 7.85 (d, 1H),7.90 (s, 1H), 8.29 (br. s., 2H)

Anal. Calcd for C₁₉H₁₇Cl₂FN₄O₃S₂.0.12C₄H₁₀: C, 45.41; H, 3.51; N, 11.01.

Found: C, 45.19; H, 3.49; N, 11.02.

Example 7973-cyano-4-[2-(5-methyl-1H-pyrazol-4-yl)-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

3-cyano-4-[2-(5-methyl-1-trityl-1H-pyrazol-4-yl)-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 428, 345 mg, 0.46 mmol) was dissolved in 4N HCl in1,4-dioxane (5 ml) and stirred at room temperature for 3 hours beforeconcentrating in vacuo. The residue obtained was purified using an ISCO™(12 g SiO₂) eluting with methanol:dichloromethane (gradient 0:1 to 1:9,by volume). The purified compound was triturated with dichloromethane(10 mL) to afford the title compound as a white solid (148 mg,34%-isolated as the hydrochloride salt).

LCMS Rt=1.84 minutes. MS m/z 507 [MH]+

¹H NMR (400 MHz, d₆-DMSO): δ 2.25 (s, 3H), 6.85 (d, 1H), 7.50 (d, 1H),7.60 (d, 1H), 7.80 (s, 2H), 7.90 (d, 1H), 8.20 (s, 1H), 8.45 (s, 1H).

Example 7984-{2-[2-(aminomethyl)pyridin-4-yl]-4-chlorophenoxy}-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

5-chloro-4-[4-chloro-2-(2-cyanopyridin-4-yl)phenoxy]-N-(2,4-dimethoxybenzyl)-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 340, 0.04 g, 0.00006 mol) was partially dissolved inmethanol (5.0 mL) and 1,4-dioxane (5.0 mL). The solution was passedthrough an H-Cube™ at 70° C. with Raney nickel catalyst (30 mmcartridge) 3 times eluting with methanol to get complete conversion.Concentration in vacuo afforded the title compound as a colourlesssolid, 0.004 g, 10% yield.

LCMS Rt=1.13 minutes. MS m/z 527.0 [M³⁵ClH]+

¹H NMR (400 MHz, CD₃OD): δ 4.11 (s, 2H), 6.52 (m 1H), 6.97 (m 1H), 7.24(m, 1H), 7.55 (m, 4H), 7.85 (s 1H), 8.59 (m, 1H)

Example 7993-Cyano-4-[2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

To a suspension of zinc dust (458 mg, 7.00 mmol) and lithium chloride(212 mg, 5.00 mmol) in tetrahydrofuran was added dibromoethane (0.043mL, 0.50 mmol) under nitrogen. The mixture was heated at 70° C. for 10minutes before cooling and adding chlorotrimethlsilane (0.013 mL, 0.10mmol). The reaction mixture was stirred for 1 hour then4-iodotetrahydro-2H-pyran (1060 mg, 5.00 mmol) was added and stirringcontinued for 18 hours. This mixture was added to a pre-stirred (10minutes) suspension of3-cyano-N-(2,4-dimethoxybenzyl)-4-[2-iodo-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 429, 11 mg, 0.3 mmol), palladium(II) acetate (6.7 mg, 0.03mmol) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (24.6 mg,0.06 mmol) in tetrahydrofuran (0.5 mL). The reaction mixture was stirredat room temperature for 2 hours before pouring into saturated aqueousammonium chloride solution (10 mL). The aqueous layer was extracted withethyl acetate (3×10 mL). The combined organic layers were dried overmagnesium sulfate and concentrated in vacuo to obtain a residue that waspurified using an ISCO™ system eluting with heptane:ethyl acetate (1:0to 4:6, by volume). The residue was dissolved in dichloromethane (3 mL)and trifluoroacetic acid (3 mL) was added. After stirring for 1 hour atroom temperature, methanol (20 mL) was added and the resultingprecipitate was filtered and the filtrate concentrated in vacuo. Thecrude material was purified using preparative HPLC to afford the titlecompound.

LCMS Rt=2.51 minutes. MS m/z 509 [MH]−

Example 8005-Chloro-2-fluoro-N-(5-fluoropyridin-2-yl)-4-[2-piperidin-4-yl-4-(trifluoromethyl)phenoxy]benzenesulfonamide

A mixture of tert-butyl4-[2-hydroxy-5-(trifluoromethyl)phenyl]piperidine-1-carboxylate(Preparation 317, 51 mg, 0.15 mmol),5-chloro-2,4-difluoro-N-(5-fluoropyridin-2-yl)-N-(methoxymethyl)benzenesulfonamide(Preparation 349, 50 mg, 0.1 mmol) and potassium carbonate (28 mg, 0.20mmol) in anhydrous dimethyl sulfoxide (2 mL) was heated at 50° C. for 30minutes. The reaction mixture was cooled to room temperature and dilutedwith ethyl acetate and water. The layers were separated and the aqueouslayer extracted with ethyl acetate. The combined extracts were washedwith saturated aqueous sodium chloride solution, water, dried overmagnesium sulfate and concentrated in vacuo to afford the title compoundas a light yellow thick oil, which was used in the next step withoutfurther purification. The residue was diluted with dichloromethane (2mL), trifluoroacetic acid (210 uL, 2.7 mmol) was added and solutionstirred at room temperature for 18 hours. The reaction solution wasconcentrated in vacuo and purified by preparative HPLC to afford thetitle compound as a white powder, 55.3 mg (as the trifluoroacetic acidsalt)

LCMS Rt=1.54 minutes. MS m/z 548 [M³⁵ClH]+

¹H NMR (CD₃OD): δ 1.94-2.32 (m, 5H), 3.09-3.28 (m, 2H), 3.47-3.63 (m,2H), 6.97-7.31 (m, 3H), 7.72-7.55 (m, 2H), 7.74 (s, 1H), 8.12 (m, 1H),8.21 (m, 1H)

Example 8014-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

4-(4-chloro-2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}phenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 688, 270 mg, 0.321 mmol) was dissolved in dichloromethane(15 ml) and N,N,N′,N′-tetramethylnaphthalene-1,8-diamine (85 mg, 0.40mmol) was added followed by 1-chloroethyl chloroformate (0.07 ml, 0.65mmol) and the solution was stirred at room temperature for 4 hours. Thesolution was concentrated in vacuo and the residue was partitionedbetween ethyl acetate (40 ml) and 1M aqueous citric acid solution (20ml), the ethyl acetate was washed with water, dried over anhydroussodium sulphate, evaporated and the solvents removed in vacuo to give anoil. The oil was dissolved in methanol (15 ml) and refluxed for 5 hours.Some of the methanol was removed in vacuo to leave about 5 ml, theprecipitated solid was removed by filtration and the filtrate wasadsorbed onto silica gel (5 g) and dried prior to purification by columnchromatography on silica gel using 10-25% v/v methanol (containing 10%v/v 0.880 aqueous ammonia) in dichloromethane. This afforded the titlecompound as a pinkish solid, 80 mg.

LCMS Rt=1.10 minutes, m/z=525 [M³⁵ClH]+; 527 [M³⁷ClH]+

¹HNMR (d₆-DMSO): δ 3.20 (brs, 3H), 4.22-4.28 (m, 4H), 5.14-5.21 (m, 1H),6.45 (d, 1H), 7.03-7.09 (m, 1H), 7.23 (d, 1H), 7.52-7.61 (m, 3H), 7.72(d, 1H), 7.89 (s, 1H), 8.75 (brs, 1H)

CHN analysis. Required for mono hydrate: C, 44.24; H, 3.16; N, 15.48.Found: C, 44.33/44.19; H, 3.22/3.22; N, 15.66/15.68

Example 801 trifluoroacetic acid salt4-[2-(1-Azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

An alternative method to the trifluoroacetic acid salt of Example 801 isprovided below:

Tert-butyl3-{5-[5-chloro-2-(4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}-2,5-difluorophenoxy)pheny]-1H-pyrazol-1-yl}azetidine-1-carboxylate,(Preparation 850, 145.47 g, 0.1455 mol) was dissolved in dichloromethane(1450 mL) and then trifluoroacetic acid (354.7 mL, 4.69 mol) was addedslowly over 30 minutes. The pink mixture was stirred at room temperaturefor 2 hours and then methanol (1450 mL) was added to give a whiteprecipitate. The solid was filtered off and the filtrate wasconcentrated in vacuo to give an oil. The oil was dissolved in a smallvolume of methanol and tert-butylmethyl ether was added very slowly withstirring to give an oily dispersion which would not crystallize. Thesolvents were removed in vacuo and the residue was dissolved in methanoland evaporated, this was repeated a further two times to give a foam.The foam was triturated with tert-butylmethyl ether, filtered off anddried to give the title compound as the trifluoroacetate salt which wasa pale yellow powder, (120 g).

HPLC Rt=2.22 minutes

¹HNMR (CD₃OD) δ 4.50-4.55 (m, 4H), 5.19-5.28 (m, 1H), 6.39 (d, 1H),6.76-6.82 (m, 1H), 7.27 (d, 1H), 7.54 (d, 1H), 7.60-7.64 (m, 1H),7.68-7.74 (m, 2H), 8.24 (s, 1H).

Example 8023-cyano-4-[2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

To a solution of3-cyano-N-(2,4-dimethoxybenzyl)-4-[2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide,(Preparation 711, 59.7 mg, 0.091 mmol) in dichloromethane (3 mL) wasadded trifluoroacetic acid (0.33 mL) The mixture was stirred overnightat room temperature under nitrogen. The reaction mixture wasconcentrated in vacuo. The purple residue was partitioned betweendichloromethane (10 mL) and water (10 mL). The aqueous layer wasextracted with dichloromethane (3×10 mL) and the combined organic layerswere washed with saturated aqueous sodium chloride solution (10 mL),dried over anhydrous sodium sulfate, filtered and the solvent removed invacuo to afford a brown solid (30.7 mg, 67%).

LCMS Rt=3.81 minutes, MS m/z 505 [MH]+

¹HNMR (d₆-DMSO): δ 7.28 (m, 1H), 7.56 (m, 1H), 7.91 (m, 1H), 7.98 (m,1H), 8.02 (m, 1H), 8.18 (m, 1H), 8.27 (m, 1H), 8.44 (s, 1H), 9.31 (m,1H), 9.45 (m, 1H).

Method 2

The sodium salt of Example 802 can also be prepared as follows.

To a solution of3-cyano-N-(2,4-dimethoxybenzyl)-4-[2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide,(Preparation 711, 18.2 g, 0.028 mol) in dichloromethane (182 mL) wasadded trifluoroacetic acid (91 mL) dropwise over 3 minutes. The mixturewas stirred for 45 minutes before addition of water (200 mL) andmethanol (200 mL). The resulting slurry was stirred at room temperaturefor 18 hours before filtration through a short pad of silica (9 cmdiameter×2 cm deep). The filtrate was concentrated in vacuo to removeorganics before addition of a saturated aqueous solution of sodiumbicarbonate (91 mL) and dichloromethane (150 mL) with vigourous stirringfor 30 minutes. The aqueous layer was extracted with methyl ethyl ketone(3×100 mL) and solid sodium bicarbonate (20 g) added to improveseparation of aqueous/organic layers. The combined organic extracts werewashed with brine (150 mL), dried over sodium sulfate before addition oftoluene (180 mL) and concentration/drying in vacuo at 50° C. Theresulting pale orange solid (14.7 g) was slurried in water (120 mL) atroom temperature for 100 minutes before filtration and drying in vacuoto provide sodium salt of the title compound as a cream coloured solid(9.6 g).

¹⁹FNMR (d₆-DMSO): δ −60.5 ppm (s).

¹HNMR (d₆-DMSO): δ 7.22 (d, 1H), 7.43 (d, 1H), 7.80-8.00 (m, 4H), 8.04(s, 1H), 8.13 (s, 1H), 9.28 (s, 1H), 9.45 (s, 1H).

Example 8034-[2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide

The title compound was prepared fromN-[1-tert-Butyl-4-(5-chloro-2-hydroxyphenyl)-1H-pyrazol-3-yl]-2,2,2-trifluoroacetamide(Preparation 209) and5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide(Preparation 247) using Method B above with the exception that heatingat 55° C. in HCl (gas) saturated methanol for 16 hours was used toremove the protecting groups. Purification by preparative HPLC affordedthe title compound.

LCMS Rt=1.61 minutes

MS m/z 503 [M³⁷ClH]+, 501 [M³⁵ClH]+

¹HNMR (d₆-DMSO): δ 4.50 (br s, 2H), 6.89 (m, 1H), 7.21 (m, 1H), 7.37 (m,1H), 7.66 (m, 1H), 7.70 (m, 1H), 7.89 (m, 1H), 8.81 (d, 1H).

Example 8044-[4-chloro-5-fluoro-2-(1H-pyrazol-4-yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

To a solution of tert-butyl4-[5-chloro-2-(2-cyano-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}phenoxy)-4-fluorophenyl]-1H-pyrazole-1-carboxylate(Preparation 728, 190 mg, 0.26 mmol) in dichloromethane (5 mL) was addedtrifluoroacetic acid (0.3 mL, 3.65 mmol) and the reaction mixture wasleft to stir at room temperature for 16 hours. The reaction was quenchedby addition of water (10 mL) and the resulting mixture left to stir for20 minutes. Then the layers were separated, the organic phase was washedwith saturated aqueous sodium chloride solution (5 mL), dried overanhydrous magnesium sulphate, filtered and concentrated in vacuo. Thecrude oil was purified using ISCO™ (5 g cartridge) 1-20% v/v gradient ofmethanol in dichloromethane as the eluent. The title compound wasobtained as a white solid (61 mg. 50%).

LCMS Rt=4.51 minutes, MS m/z 477 [M³⁵ClH]+

¹HNMR (d₆-DMSO): δ 6.95 (m, 1H), 7.10 (m, 1H), 7.55 (m, 1H), 7.80-8.01(m, 2H), 8.10 (m, 2H), 13.0 (brs, 1H).

Example 8052,5-difluoro-4-[2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

The mixture ofN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 647, 44 mg, 0.10 mmol),2-pyridazin-4-yl-4-(trifluoromethyl)phenol (Preparation 712, 34 mg, 0.10mmol), and potassium carbonate (55 mg, 0.40 mmol) inN,N-dimethylformamide (1.0 ml) was stirred at room temperature for 24hours. The reaction mixture was poured into aqueous 2 M hydrochloricacid solution (5.0 ml) and filtered to give a solid. The solid wasdissolved in dichloromethane (1.0 ml) and trifluoroacetic acid (1.0 ml)was added to the solution. The resulting solution was stirred for 16hours. Methanol (5.0 ml) was added to the reaction mixture and filteredoff polymeric solid. The filtrate was concentrated in vacuo to give aresidue. The residue was passed through a 5 g SCX™ column with 1:1dichloromethane:methanol solution and then 1:0.75:0.25dichloromethane:methanol:7N ammonia solution in methanol. The filtratewas concentrated in vacuo and purified by HPLC. Yield 7.3 mg, 14%.

LCMS Rt=2.44 minutes MS m/z 516 [MH]+

¹HNMR (400 MHz, CD₃OD): δ 7.25 (m, 1H), 7.30 (d-d, 1H), 7.80-7.85 (m,2H), 8.00 (d, 1H), 8.05 (d-d, 1H), 8.25 (s, 1H), 9.30 (d, 1H), 9.50 (s,1H)

Example 8065-Chloro-2-fluoro-4-{4-fluoro-2-[1-(1-methylazetidin-3-yl)-1H-pyrazol-5-yl]phenoxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

The title compound was prepared by analogy with Example 807 below using4-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-fluorophenoxy]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Example 810, 45 mg, 0.08 mmol).

Yield 14.5 mg 34%.

LCMS Rt=2.49 minutes, m/z 539 [M³⁵ClH]+

TLC Rf=0.5 (methyl isobutyl ketone:acetic acid:water 2:1:1)

¹HNMR (d₆-DMSO): δ 2.94 (s, 3H), 4.13-4.58 (m, 4H), 5.20 (m, 1H), 6.43(s, 1H), 6.81 (d, 1H), 7.26-7.34 (m, 1H), 7.39-7.48 (m, 2H), 7.67-7.74(m, 2H), 7.91 (s, 1H)

Example 8075-Chloro-2-fluoro-4-{4-fluoro-2-[1-(1-methylazetidin-3-yl)-1H-pyrazol-5-yl]phenoxy}-N-1,3-thiazol-4-ylbenzenesulfonamide

4-[2-(1-Azetidin-3-yl-1H-pyrazol-5-yl)-4-fluorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide(Example 808, 29 mg, 0.052 mmol) was stirred in dichloromethane (2 ml),methanol (0.2 ml), aqueous formaldehyde (0.015 ml of 37% wt/vol) addedand the reaction stirred at room temperature for a further 30 minutes.Sodium triacetoxyborohydride (37 mg, 0.172 mmol) was added and thesolution stirred for 3 hours. The solvents were removed in vacuo and theresidue dissolved in ethyl acetate and extracted with saturated aqueoussodium hydrogencarbonate solution (2×10 ml) and brine (2×10 ml). Theorganic layer was separated, dried over sodium sulphate, filtered andevaporated to give a solid. The compound was purified using preparative

HPLC to afford the title compound. Yield 15.9 mg 57%.

LCMS Rt=2.38 minutes, m/z 538 [M³⁵ClH]+

¹HNMR (CD₃OD): δ 4.25 (m, 4H), 5.25 (m, 1H), 6.34 (s, 1H), 6.92 (d, 1H)7.08 (s, 1H), 7.45 (m, 3H), 7.66 (s, 1H), 7.79 (d, 1H), 8.92 (s, 1H),9.17 (brs, 1H), 11.32 (brs, 1H).

Example 8084-[2-(1-Azetidin-3-yl-1H-pyrazol-5-yl)-4-fluorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide

The title compound was prepared by analogy with Example 809, below, fromtert-butyl{[5-chloro-4-(2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}-4-fluorophenoxy)-2-fluorophenyl]sulfonyl}1,3-thiazol-4-ylcarbamate(Preparation 683, 140 mg, 0.177 mmol). Yield 42 mg 42%.

LCMS Rt=1.04 minutes, m/z 524 [M³⁵ClH]+

¹HNMR (CD₃OD): δ 4.25 (m, 4H), 5.25 (m, 1H), 6.34 (s, 1H), 6.92 (d, 1H)7.08 (s, 1H), 7.45 (m, 3H), 7.66 (s, 1H), 7.79 (d, 1H), 8.92 (s, 1H),9.17 (brs, 1H), 11.32 (brs, 1H).

Example 8094-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy]-3-cyano-N-1,3-thiazol-4-ylbenzenesulfonamide

tert-butyl({4-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy]-3-cyanophenyl}sulfonyl)1,3-thiazol-4-ylcarbamate(Preparation 679, 200 mg, 0.326 mmol) was stirred in 4M hydrogenchloride solution in 1,4-dioxan (10 ml) at room temperature for 2 hours.The reaction mixture was concentrated in vacuo and the residue waspartitioned between methyl-t-butyl ether (80 ml) and water (40 ml). Theaqueous layer was neutralized to pH=7 by adding sodium hydrogencarbonate and was then concentrated in vacuo. The crude product waspurified by column chromatography on silica gel usingdichloromethane:methanol:0.880 aqueous ammonia, 90:10:1 to 70:30:3. Thisgave a buff powder (65 mg) which was triturated with methyl tert-butylether to give the title compound as a buff powder, 55 mg.

LCMS Rt=1.26 minutes, m/z 513 [M³⁵ClH]+; 515 [M³⁷ClH]+

NMR (d₆-DMSO) δ 3.31 (bs, 2H) 4.04-4.14 (m, 4H), 5.05-5.14 (m, 1H), 6.30(s, 1H), 6.38 (bs, 1H), 6.86 (d, 1H), 7.43 (d, 1H), 7.61 (m, 2H), 7.68(m, 1H), 7.84 (m, 1H), 8.01 (s, 1H), 8.67 (s, 1H).

Example 8104-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-fluorophenoxy]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

The title compound was prepared by analogy with Example 809, above, from5-chloro-N-(2,4-dimethoxybenzyl)-4-(2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}-4-fluorophenoxy)-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 681, 500 mg, 0.594 mmol). Final purification was achievedby suspending the solid in methanol and the mixture filtered throughCelite™ (insoluble purple solid discarded). The colourless filtrate wasevaporated and the residue triturated with diethyl ether and theoff-white solid filtered off and dried at 60° C. in vacuo to give thetitle compound. Yield 113 mg 34%.

LCMS Rt=1.10 minutes, m/z 525 [M³⁵ClH]+

¹HNMR (d₆-DMSO): δ 4.27 (m, 4H), 5.23 (m, 1H), 6.40 (s, 1H), 6.92 (d,1H) 7.34 (m, 1H), 7.45 (m, 2H), 7.69 (s, 1H), 7.79 (d, 1H), 8.35 (s,1H), 8.72 (brs, 1H), 9.10 (brs, 1H).

¹⁹FNMR (d₆-DMSO) δ 74.39 (s, 3F) 106.9 (s, 1F) 116.7 (s, 1F).

TLC Rf=0.5 (methyl isobutyl ketone:acetic acid:water 2:1:1)

Example 8114-{4-Chloro-2-[1-(1-methylazetidin-3-yl)-1H-pyrazol-5-yl]phenoxy}-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

4-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Example 801, 54 mg, 0.1 mmol) was stirred with dichloromethane (2 mL)methanol (0.2 mL) and 37% w/v aqueous formaldehyde solution (0.025 mL,0.34 mmol) at room temperature for 15 minutes. Sodiumtriacetoxyborohydride (68 mg, 0.32 mmol) was added at the reactionstirred at room temperature for 18 hours. 37% wt/vol aqueousformaldehyde solution (0.025 mL, 0.34 mmol) was added and the reactionstirred for 15 minutes then sodium triacetoxyborohydride (68 mg, 0.32mmol) was added at the reaction stirred at room temperature for 3 hours.The mixture was evaporated and the residue dissolved in ethyl acetate(20 mL) and washed with saturated aqueous sodium bicarbonate solution(2×10 ml) and saturated aqueous sodium chloride solution (2×10 ml). Theorganic layer was separated, dried over sodium sulphate, filtered andevaporated to give a solid. The solid was suspended in methyl isobutylketone:acetic acid:water 2:1:1 and eluted through a silica column (5 g)with methyl isobutyl ketone:acetic acid:water 2:1:1. The appropriatefractions were combined and concentrated in vacuo to give a film. Thiswas scratched with ethyl acetate then diethyl ether and dried in vacuoto give the title compound as a white solid. Yield 30 mg. 54%.

LCMS Rt=1.11 minutes, m/z 539 [M³⁵ClH]+

¹HNMR (d₆-DMSO): δ 2.80 (s, 3H), 4.10 (m 2H) 4.24 (m 2H) 5.05 (m 1H)6.43 (d 1H) 7.07 (m 1H) 7.22 (d 1H) 7.57 (m, 3H) 7.69 (s 1H) 7.89 (s,1H),

TLC Rf=0.5 (methyl isobutyl ketone:acetic acid:water 2:1:1)

Example 811 sodium salt4-{4-Chloro-2-[1-(1-methylazetidin-3-yl)-1H-pyrazol-5-yl]phenoxy}-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamidesodium salt

The sodium salt of Example 811 was prepared as follows:4-{4-Chloro-2-[1-(1-methylazetidin-3-yl)-1H-pyrazol-5-yl]phenoxy}-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide,(Example 811, 35.0 g, 0.06494 mol) was suspended in water (210 mL) and asolution of sodium hydroxide (2.47 g, 0.06169 mol) in water (210 mL) wasadded dropwise over 10 minutes. The resulting cloudy solution wasfiltered and the water removed in vacuo to give a white foam. The foamwas triturated with tert-butylmethyl ether and the white solid filteredoff and dried to give the title compound as a white powder, (28.85 g).

¹HNMR (d₆-DMSO) δ 2.27 (s, 3H), 3.29-3.35 (m, 2H), 3.54-3.59 (m, 2H),4.70-4.79 (m, 1H), 6.34 (d, 1H), 7.04-7.10 (m, 1H), 7.18-7.21 (d, 1H),7.49 (d, 1H), 7.53-7.60 (m, 3H), 7.90 (s, 1H).

Example 8114-{4-Chloro-2-[1-(1-methylazetidin-3-yl)-1H-pyrazol-5-yl]phenoxy}-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

An alternative method of preparing Example 811 is as follows:4-[2-(1-Azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamidetrifluoroacetate salt, (Example 801, 110.45 g, 0.1558 mol) was dissolvedin dichloromethane (1050 mL) and methanol (110.45 mL). Acetic acid(17.86 mL, 2.73 mol) was added followed by aqueous formaldehyde solution(58.54 mL of 37 wt % in water, 0.779 mol), stirred at room temperaturefor 30 minutes. The solution was then cooled in an ice bath and sodiumtriacetoxyborohydride (82.56 g, 0.3895 mol) was added, stirred whilstwarming to room temperature over 1.5 hours. Aqueous formaldehydesolution (29.27 mL of 37 wt % in water, 0.3895 mol) was added, stirredfor 30 minutes then sodium triacetoxyborohydride (82.56 g, 0.3895 mol)was added and stirred at room temperature for 1.5 hours. The reactionwas quenched by adding water (552.25 mL) and stirred for 30 minutes then0.880 aqueous ammonia solution (100 mL) was added in two equal portionsand stirred for a further 30 minutes. The resulting solid was filteredoff and dried to give the crude title compound as a white solid, (135g). The crude product was suspended in ethanol (405 mL) and heated toreflux for 1 hour then water (405 mL) was added and the resulting slurrywas stirred at 90° C. for 30 minutes before being allowed to cool to 35°C. The solid was filtered off and dried to give the title compound as awhite solid, (67.5 g).

HPLC Rt=2.43 minutes

LCMS Rt=2.11 minutes, m/z=539 [M³⁵ClH]+

¹HNMR (d₆-DMSO) δ 2.96 (s, 3H), 4.28-4.35 (m, 2H), 4.42-4.51 (m, 2H),5.11-5.21 (m, 1H), 6.47 (d, 1H), 7.04-7.10 (m, 1H), 7.24-7.26 (m, 1H),7.55-7.62 (m, 3H), 7.73 (d, 1H), 7.92 (s, 1H).

Example 8124-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-pyrimidin-4-ylbenzenesulfonamide

The title compound was prepared by analogy with the method used forExample 813 below using5-chloro-N-(ethoxymethyl)-2,4-difluoro-N-pyrimidin-4-ylbenzenesulfonamide,5-chloro-N-[(4E)-1-(ethoxymethyl)pyrimidin-4(1H)-ylidene]-2,4-difluorobenzenesulfonamideand5-chloro-N-[(4E)-1-(ethoxymethyl)pyrimidin-4(1H)-ylidene]-2,4-difluorobenzenesulfonamide,(Preparation 719) used as a mixture of three regioisomers and2-(2-aminopyridin-4-yl)-4-chlorophenol (Preparation 721).

LCMS Rt=1.39 minutes, MS m/z 506 [MH]+

¹HNMR (d₆-DMSO): δ 6.90-7.02 (m, 2H), 7.05 (s, 1H), 7.21-7.29 (m, 2H),7.66 (dd, 1H), 7.77 (d, 1H), 7.90-8.30 (m, 4H), 8.62 (s, 1H).

Example 8135-chloro-4-[4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]-2-fluoro-N-pyrimidin-4-ylbenzenesulfonamide

A suspension of5-chloro-N-(ethoxymethyl)-2,4-difluoro-N-pyrimidin-4-ylbenzenesulfonamideand5-chloro-N-[(4E)-1-(ethoxymethyl)pyrimidin-4(1H)-ylidene]-2,4-difluorobenzenesulfonamideand5-chloro-N-[(4E)-1-(ethoxymethyl)pyrimidin-4(1H)-ylidene]-2,4-difluorobenzenesulfonamide(Preparation 719) used as a mixture of three regioisomers, (64 mg, 0.18mmol), 4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenol (Preparation 89) (37mg, 0.18 mmol) and potassium carbonate (37 mg, 0.26 mmol) in dimethylsulfoxide (1 mL) was stirred at room temperature for 19 hours thendiluted with ethyl acetate (30 mL), washed with 1M aqueous sodiumhydroxide, water, saturated aqueous sodium chloride solution, dried overanhydrous sodium sulfate and concentrated in vacuo. The residue wastaken up in trifluoroacetic acid (1 mL) and stirred for 3 hours thenconcentrated in vacuo. The residue was purified by reverse phase HPLC togive 29 mg (27%) of the desired product as a white solid.

LCMS Rt=1.67 minutes MS m/z 494 [MH]+

¹HNMR (d₆-DMSO): δ 3.77 (s, 3H), 6.33 (d, 1H), 6.96-7.02 (m, 2H), 7.32(d, 1H), 7.41 (d, 1H), 7.55-7.65 (m, 2H), 7.96 (d, 1H), 8.25 (d, 1H),8.60 (s, 1H).

Example 8144-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide

The title compound was prepared from2-(2-aminopyridin-4-yl)-4-chlorophenol, (Preparation 721) and5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide(Preparation 247) using a method analogous to that used in Preparation669. Purification by semi-preparative HPLC using 15-100% MeOH/H₂Oyielded the title compound.

LCMS Rt=1.47 minutes, MS m/z 512 [MH]+

¹HNMR (d₆-DMSO): δ 6.96 (m, 1H), 7.04 (m, 1H), 7.23 (m, 2H), 7.60 (m,1H), 7.73 (d, 1H), 7.91 (m, 2H), 8.83 (m, 1H).

Yet further examples of the present invention were prepared, again usingmethods analogous to the General Schemes described above, LibraryProtocols 1 and 2 described above, and Methods A-M as described forExamples 1-6, 95-99, 134, 170, and 279 above, or any of the other fullywritten up experimental conditions provided, substituting appropriatestarting materials where necessary and making appropriate changes toexperimental conditions informed by the schemes and conditions providedand common general knowledge. Purification was performed either bysilica gel column chromatography, trituration or preparative HPLC.

MS m/z Unless Eg otherwise No Name stated 8154-{[3′-(azetidin-1-ylmethyl)-5- 630 [MH]+iodobiphenyl-2-yl]oxy}-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 8165-chloro-4-[4-chloro-2-(5-methyl-1H- 500 [M³⁵ClH]+pyrazol-4-yl)phenoxy]-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide 8175-chloro-4-[4-chloro-2-(1-methyl-1H- 514 [M³⁵ClH]+pyrazol-5-yl)phenoxy]-2-fluoro-N-(5- methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide 818 4-[2-(2-aminopyridin-4-yl)-4- 485 [MH]+chlorophenoxy]-3-cyano-N-1,3,4- thiadiazol-2-ylbenzenesulfonamide 8195-chloro-4-{4-chloro-2-[1-(2- 544 [M³⁵ClH]+methoxyethyl)-1H-pyrazol-3-yl]phenoxy}- 2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide 820 4-[2-(2-aminopyridin-4-yl)-4- 496 [MH]+chlorophenoxy]-2,5-difluoro-N-1,3,4- thiadiazol-2-ylbenzenesulfonamide821 4-[4-chloro-2-(1H-pyrazol-4-yl)phenoxy]- 470 [M³⁵ClH]+2,5-difluoro-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 8224-{[3′-(azetidin-1-ylmethyl)-5- 565 [M³⁵ClH]+chlorobiphenyl-2-yl]oxy}-5-chloro-2- fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide 823 4-{[3′-(azetidin-1-ylcarbonyl)-5- 579 [M³⁵ClH]+chlorobiphenyl-2-yl]oxy}-5-chloro-2- fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 824 5-chloro-4-({5-chloro-3′-[(3- 595 [M³⁵ClH]+hydroxyazetidin-1-yl)carbonyl]biphenyl-2-yl}oxy)-2-fluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 8254-[4-chloro-2-(tetrahydro-2H-pyran-4- 470 [M³⁵ClH]+yl)phenoxy]-3-fluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 8264-[2-(3-amino-1H-pyrazol-5-yl)-4- 458 [MH]+fluorophenoxy]-3-cyano-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide 8274-[4-chloro-2-(1-cyclopropyl-1H-pyrazol- 498 [MH]−5-yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol- 5-ylbenzenesulfonamide 8284-[4-chloro-2-(1-cyclobutyl-1H-pyrazol-5- 512 [MH]−yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 8293-fluoro-4-[2-(1H-pyrazol-5-yl)-4- 502 [MH]+(trifluoromethoxy)phenoxy]-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide830 4-[2-(6-aminopyridin-2-yl)-4- 546 [MH]+(trifluoromethoxy)phenoxy]-2,5-difluoro- N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 831 4-{2-[6-(azetidin-1-ylmethyl)pyridin-2-yl]- 566[MH]+ 4-chlorophenoxy}-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide 8324-(4-chloro-2-pyridazin-4-ylphenoxy)-3- 471 [MH]+cyano-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 8334-[4-chloro-2-(2-piperazin-1-ylpyridin-4- 565 [M³⁵ClH]+yl)phenoxy]-2,5-difluoro-N-1,3,4- thiadiazol-2-ylbenzenesulfonamide 8344-[4-chloro-2-(2-piperazin-1-ylpyridin-4- 553 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3-thiazol-4- ylbenzenesulfonamide 8354-[4-chloro-2-(2-piperazin-1-ylpyridin-4- 554 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 8364-[4-chloro-2-(tetrahydro-2H-pyran-4- 477 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 8374-[4-(difluoromethoxy)-2-(1H-pyrazol-4- 502 [MH]+yl)phenoxy]-2,5-difluoro-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide 8384-{2-[2-(azetidin-1-ylmethyl)pyridin-4-yl]- 550 [M³⁵ClH]+4-chlorophenoxy}-2,5-difluoro-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide839 4-[4-chloro-2-(1H-pyrazol-4-yl)phenoxy]- 459 [M³⁵ClH]+3-cyano-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 8404-[2-(3-amino-1H-pyrazol-5-yl)-4- 485 [M³⁵ClH]+fluorophenoxy]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 8414-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4- 558 [MH]+(trifluoromethyl)phenoxy]-2,5-difluoro-N-1,3-thiazol-4-ylbenzenesulfonamide 8423-cyano-4-[4-fluoro-2-(tetrahydro-2H- 461 [MH]+pyran-4-yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 8435-chloro-4-(4-chloro-2-pyridazin-4- 498 [MH]+ylphenoxy)-2-fluoro-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 8444-{4-chloro-2-[1-(1-methylazetidin-3-yl)- 539 [MH]+1H-pyrazol-5-yl]phenoxy}-2,5-difluoro-N-1,3-thiazol-4-ylbenzenesulfonamide 8455-chloro-4-(4-chloro-2-pyridazin-4- 497 [MH]+ylphenoxy)-2-fluoro-N-1,3-thiazol-4- ylbenzenesulfonamide 8464-(4-chloro-2-pyridazin-4-ylphenoxy)-2,5- 493 [M³⁵ClH]+difluoro-N-(5-fluoropyridin-2- yl)benzenesulfonamide 8473-chloro-4-(4-chloro-2-pyridazin-4- 474 [M³⁵ClH]+ylphenoxy)-N-pyrimidin-4- ylbenzenesulfonamide 8485-chloro-4-{2-[1-(1-ethylazetidin-3-yl)- 553 [M³⁵ClH]+1H-pyrazol-5-yl]-4-fluorophenoxy}-2- fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 849 4-[2-(2-aminopyrimidin-4-yl)-4- 497 [M³⁵ClH]+chlorophenoxy]-2,5-difluoro-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide850 5-chloro-4-[4-cyano-2-(1H-pyrazol-4- 477 [M³⁵ClH]+yl)phenoxy]-2-fluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 8514-{4-chloro-2-[1-(1-ethylazetidin-3-yl)- 552 [MH]+1H-pyrazol-5-yl]phenoxy}-2,5-difluoro-N-1,3-thiazol-4-ylbenzenesulfonamide 852 4-{[3′-(azetidin-1-ylmethyl)-5-538 [MH]+ chlorobiphenyl-2-yl]oxy}-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 8534-[4-chloro-2-(5-cyanopyridin-2- 495 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 8544-{[3′-(azetidin-1-ylcarbonyl)-5- 552 [M³⁵ClH]+chlorobiphenyl-2-yl]oxy}-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 8554-{[3′-(azetidin-1-ylcarbonyl)-5- 563 [M³⁵ClH]+chlorobiphenyl-2-yl]oxy}-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 8564-{[3′-(azetidin-1-ylcarbonyl)-5- 578 [M³⁵ClH]+chlorobiphenyl-2-yl]oxy}-5-chloro-2- fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide 857 4-{[3′-(azetidin-1-ylcarbonyl)-5- 579 [M³⁵ClH]+chlorobiphenyl-2-yl]oxy}-5-chloro-2- fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide 858 4-{[3′-(azetidin-1-ylcarbonyl)-5- 555 [M³⁵ClH]+chlorobiphenyl-2-yl]oxy}-3-chloro-N- pyrimidin-4-ylbenzenesulfonamide859 4-{2-[6-(azetidin-1-ylcarbonyl)pyridin-2- 580 [M³⁵ClH]+yl]-4-chlorophenoxy}-5-chloro-2-fluoro- N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 860 5-chloro-4-{4-chloro-2-[3-(dimethyl- 528[M³⁵ClH]+ amino)-1H-pyrazol-4-yl]phenoxy}-2- fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide 861 4-{4-chloro-2-[1-(1-isopropylazetidin-3- 555[MH]+ yl)-1H-pyrazol-5-yl]phenoxy}-3-cyano-N-1,3-thiazol-4-ylbenzenesulfonamide 8623-chloro-4-[4-chloro-2-(1-methyl-1H- 476 [M³⁵ClH]+pyrazol-5-yl)phenoxy]-N-pyridazin-3- ylbenzenesulfonamide 8634-[4-chloro-5-fluoro-2-(5-methyl-1H- 491 [M³⁵ClH]+pyrazol-4-yl)phenoxy]-3-cyano-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide864 5′-chloro-2′-{2-cyano-4-[(1,2,4-thiadiazol- 552 [MH]+5-ylamino)sulfonyl]phenoxy}-N- cyclopropylbiphenyl-3-carboxamide 8654-[4-chloro-2-(5-methyl-1H-pyrazol-4- 473 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 8664-{4-chloro-2-[1-(1,1-dioxidotetrahydro-3- 588 [M³⁵ClH]+thienyl)-1H-pyrazol-5-yl]phenoxy}-2,5- difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 867 4-[(3′-{[3,3-bis(hydroxymethyl)azetidin-1- 598[MH]+ yl]methyl}-5-chlorobiphenyl-2-yl)oxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 8684-(4-chloro-2-pyridazin-4-ylphenoxy)-3- 471 [M³⁵ClH]+cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 8693-chloro-4-(4-chloro-2-pyridazin-4- 474 [M³⁵ClH]+ylphenoxy)-N-pyridazin-3- ylbenzenesulfonamide 8705-chloro-4-{4-chloro-2-[3- 529 [M³⁵ClH]+ (dimethylamino)-1H-pyrazol-4-yl]phenoxy}-2-fluoro-N-1,3,4-thiadiazol- 2-ylbenzenesulfonamide 8715-chloro-2-fluoro-N-(3-methyl-1,2,4- 546 [M³⁵ClH]+thiadiazol-5-yl)-4-[2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]benzene- sulfonamide 8724-[2-(3-amino-1H-pyrazol-4-yl)-4- 515 [M³⁵ClH]+chlorophenoxy]-5-chloro-2-fluoro-N-(3- methyl-1,2,4-thiadiazol-5-yl)benzenesulfonamide 873 4-[4-chloro-2-(6-morpholin-4-ylpyrimidin- 567[M³⁵ClH]+ 4-yl)phenoxy]-2,5-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide 8744-(4-chloro-2-{6-[(3,3-difluoroazetidin-1- 575 [MH]+yl)methyl]pyridin-2-yl}phenoxy)-3-cyano- N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 875 4-[4-chloro-2-(6-piperazin-1-ylpyrimidin- 555[M³⁵ClH]+ 4-yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 876 4-[4-chloro-2-(6-morpholin-4-ylpyrimidin- 556[M³⁵ClH]+ 4-yl)phenoxy]-3-cyano-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide 877 4-[2-(6-azetidin-1-ylpyrimidin-4-yl)-4- 526[M³⁵ClH]+ chlorophenoxy]-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 878 3-cyano-4-[2-pyridazin-4-yl-4- 521[MH]+ (trifluoromethoxy)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 8794-(4-chloro-2-pyridazin-4-ylphenoxy)-2,5- 482 [M³⁵ClH]+difluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 8804-(4-chloro-2-isoxazol-3-ylphenoxy)-3- 460 [M³⁵ClH]+cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 8814-[4-chloro-2-(1-methyl-1H-pyrazol-5- 467 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-pyrimidin-2- ylbenzenesulfonamide 8824-{4-chloro-2-[1-(tetrahydrofuran-3-yl)- 529 [M³⁵ClH]+1H-pyrazol-5-yl]phenoxy}-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 8834-[4-chloro-2-(1-methyl-1H-pyrazol-5- 470 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-(5- methylisoxazol-3-yl)benzenesulfonamide 8845-chloro-4-{4-chloro-2-[1-(1- 555 [M³⁵ClH]+methylazetidin-3-yl)-1H-pyrazol-5-yl]phenoxy}-2-fluoro-N-1,3,4-thiadiazol- 2-ylbenzenesulfonamide 8854-[4-chloro-2-(1-methyl-1H-pyrazol-5- 467 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-pyrazin-2- ylbenzenesulfonamide 8864-[4-chloro-2-(1-methyl-1H-pyrazol-5- 517 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-(5-ethoxy-1,3,4-thiadiazol-2-yl)benzenesulfonamide 8874-[4-chloro-2-(1-methyl-1H-pyrazol-5- 469 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-(1-methyl-1H- pyrazol-3-yl)benzenesulfonamide 8884-[4-chloro-2-(1-methyl-1H-pyrazol-5- 487 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide 8893-cyano-4-[4-fluoro-2-(1,3-oxazol-4- 444 [MH]+yl)phenoxy]-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 8905-chloro-4-[4-cyano-2-(1H-pyrazol-5- 475 [M³⁵ClH]−yl)phenoxy]-2-fluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 8914-[4-chloro-2-(1-methyl-1H-pyrazol-5- 519 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-[5-(methylthio)-1,3,4-thiadiazol-2-yl]benzenesulfonamide 8924-[4-chloro-2-(1-methyl-1H-pyrazol-5- 481 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-(5-methylpyrazin- 2-yl)benzenesulfonamide 8934-[4-chloro-2-(1-methyl-1H-pyrazol-5- 519 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-[5-(methylthio)-1,2,4-thiadiazol-3-yl]benzenesulfonamide 8944-[4-chloro-2-(1-methyl-1H-pyrazol-5- 469 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-(1-methyl-1H- pyrazol-5-yl)benzenesulfonamide 8954-[4-chloro-2-(1-methyl-1H-pyrazol-5- 467 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-pyrimidin-5- ylbenzenesulfonamide 8964-[4-chloro-2-(6-morpholin-4-ylpyrimidin- 556 [M³⁵ClH]+4-yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol- 5-ylbenzenesulfonamide 8972,5-difluoro-4-[2-pyridazin-4-yl-4- 532 [MH]+(trifluoromethoxy)phenoxy]-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide898 3-chloro-4-(4-chloro-2-pyridazin-4- 480 [M³⁵ClH]+ylphenoxy)-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 8994-[4-chloro-2-(2-morpholin-4-ylpyridin-4- 555 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 9003-chloro-4-[2-pyridazin-4-yl-4- 530 [M³⁵ClH]+(trifluoromethoxy)phenoxy]-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide901 3-cyano-4-[2-pyridazin-3-yl-4- 505 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide 9024-{4-chloro-2-[2-(cyclobutyl- 539, 541 [MH]+amino)pyridin-4-yl]phenoxy}-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 9033-cyano-4-[2-pyrimidin-4-yl-4- 505 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide 9044-[2-(6-chloropyridazin-3-yl)-4- 550 [M³⁵ClH]+(trifluoromethyl)phenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 9054-(4-chloro-2-isothiazol-3-ylphenoxy)-3- 476 [M³⁵ClH]+cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 9064-(2-azetidin-3-yl-4-chlorophenoxy)-3- 448 [M³⁵ClH]+cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 9074-[4-chloro-2-(1-methyl-1H-pyrazol-5- 471 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-(4-methyl-1,2,5- oxadiazol-3-yl)benzenesulfonamide908 4-[4-chloro-2-(1-methyl-6-oxo-1,6- 500 [MH]+dihydropyridin-3-yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 9095-chloro-2-fluoro-4-[2-pyridazin-4-yl-4- 548 [M³⁵ClH]+(trifluoromethoxy)phenoxy]-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide910 5-chloro-4-(4-chloro-2-pyridazin-4- 498 [M³⁵ClH]+ylphenoxy)-2-fluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 9113-chloro-4-[4-chloro-2-(1H-pyrazol-5- 467 [M³⁵ClH]+yl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 9124-[2-(5-amino-1H-pyrazol-4-yl)-4- 482 [M³⁵ClH]+chlorophenoxy]-3-chloro-N-1,3-thiazol-4- ylbenzenesulfonamide 9134-[2-(5-amino-1H-pyrazol-4-yl)-4- 483 [M³⁵ClH]+chlorophenoxy]-3-chloro-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide 9144-[4-chloro-2-(5-methylpyridazin-4- 485 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 9154-[4-chloro-2-(1-methyl-1H-pyrazol-5- 467 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-pyridazin-3- ylbenzenesulfonamide 9164-[4-chloro-2-(1-methyl-1H-pyrazol-5- 497 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-(3-methoxy- pyrazin-2-yl)benzenesulfonamide 9172,5-difluoro-4-[2-pyridazin-4-yl-4- 516 [MH]+(trifluoromethyl)phenoxy]-N-1,3,4- thiadiazol-2-ylbenzenesulfonamide 9184-[2-(2-aminopyridin-4-yl)-4- 506 [M³⁵ClH]+chlorophenoxy]-5-chloro-2-fluoro-N- pyrazin-2-ylbenzenesulfonamide 9194-[2-(2-azetidin-1-ylpyridin-4-yl)-4- 525 [M³⁵ClH]+chlorophenoxy]-3-cyano-N-1,3,4- thiadiazol-2-ylbenzenesulfonamide 9202,5-difluoro-4-[2-pyridazin-3-yl-4- 516 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide 9214-[4-chloro-2-(1-methyl-1H-pyrazol-5- 473 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,2,5-thiadiazol-3- ylbenzenesulfonamide 9224-[4-chloro-2-(1-methyl-1H-pyrazol-5- 455 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1H-pyrazol-3- ylbenzenesulfonamide 9234-[4-chloro-2-(1-methyl-1H-pyrazol-5- 466 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-pyridin-3- ylbenzenesulfonamide 9244-(4-chloro-5-fluoro-2-pyridazin-4- 489 [M³⁵ClH]+ylphenoxy)-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 9255-chloro-4-(4-cyano-2-pyridazin-4- 489 [M³⁵ClH]+ylphenoxy)-2-fluoro-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 9264-[2-(2-aminopyridin-4-yl)-4- 506 [M³⁵ClH]+chlorophenoxy]-5-chloro-2-fluoro-N- pyrimidin-2-ylbenzenesulfonamide 9275-chloro-6-[4-chloro-2-(1-methyl-1H- 483 [M³⁵ClH]+pyrazol-5-yl)phenoxy]-N-1,2,4-thiadiazol- 5-ylpyridine-3-sulfonamide 9283-chloro-4-[2-pyridazin-4-yl-4- 514 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide 9293-fluoro-4-[2-pyridazin-4-yl-4- 498 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide 9304-(4-chloro-5-fluoro-2-pyridazin-4- NMR data was:ylphenoxy)-3-fluoro-N-1,2,4-thiadiazol-5- 1H NMR ylbenzenesulfonamide(CD₃OD): δ 6.95 (1H, m), 7.25 (1H, m), 7.73 (2H, m), 7.85 (1H, m), 7.96(2H, m), 9.20 (1H, m), 9.42 (1H, m). 9312,5-difluoro-4-(4-fluoro-2-pyridazin-4- 466 [MH]+ylphenoxy)-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 9325-chloro-2-fluoro-4-[2-pyridazin-4-yl-4- 548 [M³⁵ClH]+(trifluoromethoxy)phenoxy]-N-1,3,4- thiadiazol-2-ylbenzenesulfonamide933 3-cyano-4-[2-pyridazin-4-yl-4- 521 [MH]+(trifluoromethoxy)phenoxy]-N-1,3,4- thiadiazol-2-ylbenzenesulfonamide934 4-(5-chloro-4-fluoro-2-pyridazin-4- 482 [M³⁵ClH]+ylphenoxy)-3-fluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 9354-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4- 548 [MH]+(trifluoromethyl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 9364-(4-chloro-5-fluoro-2-pyridazin-4- 500 [M³⁵ClH]+ylphenoxy)-2,5-difluoro-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide 9374-(5-chloro-4-fluoro-2-pyridazin-4- 500 [M³⁵ClH]+ylphenoxy)-2,5-difluoro-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide 9384-(5-chloro-4-fluoro-2-pyridazin-4- 489 [M³⁵ClH]+ylphenoxy)-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 9395-chloro-2-fluoro-4-[2-pyridazin-4-yl-5- 532 [M³⁵ClH]+(trifluoromethyl)phenoxy]-N-1,3,4- thiadiazol-2-ylbenzenesulfonamide 9403-cyano-4-[2-pyridazin-4-yl-5- 505 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide 9415-chloro-4-(4-chloro-2-pyridazin-4- 492 [M³⁵ClH]+ylphenoxy)-2-fluoro-N-pyrimidin-2- ylbenzenesulfonamide 9423-chloro-4-[2-pyridazin-4-yl-4- 530 [M³⁵ClH]+(trifluoromethoxy)phenoxy]-N-1,3,4- thiadiazol-2-ylbenzenesulfonamide943 4-(4-chloro-2-pyridazin-4-ylphenoxy)-2- 478 [M³⁵ClH]+fluoro-5-methyl-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 9444-[2-(2-aminopyridin-4-yl)-4- 488 [M³⁵ClH]+chlorophenoxy]-3-chloro-N-pyrimidin-4- ylbenzenesulfonamide 9455-chloro-2-fluoro-4-[2-pyridazin-4-yl-4- 542 [M³⁵ClH]+(trifluoromethoxy)phenoxy]-N-pyrimidin- 2-ylbenzenesulfonamide 9463-cyano-4-[2-pyridazin-4-yl-4- 505 [MH]+(trifluoromethyl)phenoxy]-N-1,3,4- thiadiazol-2-ylbenzenesulfonamide 9475-chloro-2-fluoro-4-[4-fluoro-2-pyridazin- 550 [M³⁵ClH]+4-yl-5-(trifluoromethyl)phenoxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide 9483-cyano-4-[4-fluoro-2-pyridazin-4-yl-5- 523 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide 9494-[2-(2-aminopyridin-4-yl)-4- 490 [M³⁵ClH]+fluorophenoxy]-5-chloro-2-fluoro-N- pyrimidin-2-ylbenzenesulfonamide 9506-[4-chloro-2-(1-methyl-1H-pyrazol-5- 449 [M³⁵ClH]+yl)phenoxy]-N-1,2,4-thiadiazol-5- ylpyridine-3-sulfonamide 9515-chloro-4-(5-cyano-2-pyridazin-4- 489 [M³⁵ClH]+ylphenoxy)-2-fluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 9525-chloro-2-fluoro-4-[2-pyridazin-4-yl-4- 531 [MH]+(trifluoromethyl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 9533-cyano-4-[2-pyridazin-4-yl-4- 504 [MH]+(trifluoromethyl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 9542,5-difluoro-4-[2-pyridazin-4-yl-4- 515 [MH]+(trifluoromethyl)phenoxy]-N-1,3-thiazol-4- ylbenzenesulfonamide 9553-chloro-4-[4-chloro-2-(1-methyl-1H- 476 [M³⁵ClH]+pyrazol-5-yl)phenoxy]-N-pyrimidin-2- ylbenzenesulfonamide 9565-chloro-4-(4-chloro-3-fluoro-2-pyridazin- 516 [MH]+4-ylphenoxy)-2-fluoro-N-1,3,4-thiadiazol- 2-ylbenzenesulfonamide 9573-cyano-4-[2-pyridazin-4-yl-5- 521 [MH]+(trifluoromethoxy)phenoxy]-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide958 3-cyano-4-[5-fluoro-2-pyridazin-4-yl-4- 539 [MH]+(trifluoromethoxy)phenoxy]-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide959 3-cyano-4-{2-[1-(1-ethylazetidin-3-yl)-1H- 573 [MH]−pyrazol-5-yl]-4- (trifluoromethyl)phenoxy}-N-1,3-thiazol-4-ylbenzenesulfonamide 960 3-cyano-4-[2-pyridin-4-yl-4- 504 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide 9614-[4-chloro-2-(3-methylisoxazol-4- 474 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 9624-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4- 563 [MH]+(trifluoromethoxy)phenoxy]-3-cyano-N- 1,3-thiazol-4-ylbenzenesulfonamide963 5-chloro-2-fluoro-4-[5-fluoro-2-pyridazin- 566 [M³⁵ClH]+4-yl-4-(trifluoromethoxy)phenoxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide 9643-cyano-4-[4-fluoro-2-pyridazin-4-yl-5- 539 [MH]+(trifluoromethoxy)phenoxy]-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide965 5-chloro-2-fluoro-4-[4-fluoro-2-pyridazin- 566 [M³⁵ClH]+4-yl-5-(trifluoromethoxy)phenoxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide 9665-chloro-2-fluoro-4-[2-pyridazin-4-yl-5- 548 [M³⁵ClH]+(trifluoromethoxy)phenoxy]-N-1,3,4- thiadiazol-2-ylbenzenesulfonamide967 4-[4-chloro-2-(1,3-oxazol-5-yl)phenoxy]- 460 [M³⁵ClH]+3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 9685-chloro-6-{4-chloro-2-[1-(1- 538 [M³⁵ClH]+methylazetidin-3-yl)-1H-pyrazol-5- yl]phenoxy}-N-1,2,4-thiadiazol-5-ylpyridine-3-sulfonamide 969 4-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-547 [MH]+ (trifluoromethyl)phenoxy]-3-cyano-N-1,3-thiazol-4-ylbenzenesulfonamide 9704-[4-chloro-2-(1,3-oxazol-5-yl)phenoxy]- 471 [M³⁵ClH]+2,5-difluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 9713-cyano-4-(4,5-dichloro-2-pyridazin-4- 505 [M³⁵ClH]+ylphenoxy)-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 9724-[2-(2-aminopyridin-4-yl)-4- 490 [M³⁵ClH]+fluorophenoxy]-5-chloro-2-fluoro-N- pyrimidin-4-ylbenzenesulfonamide 9734-[2-(3-amino-1H-pyrazol-4-yl)-4- 477 [M³⁵ClH]+chlorophenoxy]-3-chloro-N-pyrimidin-4- ylbenzenesulfonamide 9745-chloro-6-[2-pyridazin-4-yl-4- 515 [M³⁵ClH]+(trifluoromethyl)phenoxy]-N-1,2,4- thiadiazol-5-ylpyridine-3-sulfonamide975 4-{4-chloro-2-[1-(1-ethylazetidin-3-yl)- 553 [MH]+1H-pyrazol-5-yl]phenoxy}-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 9764-[2-pyridazin-4-yl-4-(trifluorometh- 548 [MH]+yl)phenoxy]-N-1,2,4-thiadiazol-5-yl-3-(trifluoromethyl)benzenesulfonamide 977 3-cyano-4-[2-pyridin-3-yl-4- 502[MH]− (trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 9782-fluoro-5-methyl-4-[2-pyridazin-4-yl-4- 512 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide 9793-cyano-4-[2-(1-oxidopyridin-3-yl)-4- 520 [MH]+(trifluoromethyl)phenoxy]-N-1,2,4- thiadiazol-5-ylbenzenesulfonamide 9804-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4- 524, 526 [MH]+chlorophenoxy]-2,5-difluoro-N-1,3- thiazol-4-ylbenzenesulfonamide 9813-cyano-4-[2-(3-furyl)-4- 493 [MH]+ (trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 9824-[2-(1-tert-butyl-3-methyl-1H-pyrazol-4- 556 [MCl35H]+yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide 9832-[2-(3-methyl-1H-pyrazol-4-yl)phenoxy]- 456 [MH]+ 5-[(1,3-thiazol-2-ylamino)sulfonyl]benzamide 984 4-[4-chloro-2-(3-ethoxy-1H-pyrazol-4- 513[M³⁵ClH]+ yl)phenoxy]-2,5-difluoro-N-1,3-thiazol-4- ylbenzenesulfonamide985 3-cyano-4-(2-pyrimidin-5-ylphenoxy)-N- 436 [MH]+1,3-thiazol-2-ylbenzenesulfonamide 9864-{4-[5-amino-1-(2,2,2-trifluoroethyl)-1H- 521 [MH]+pyrazol-4-yl]phenoxy}-3-cyano-N-1,3- thiazol-2-ylbenzenesulfonamide 9873-cyano-4-{[3′-{[(3R)-3- 602 [MH]+ hydroxypyrrolidin-1-yl]methyl}-5-(trifluoromethyl)biphenyl-2-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 9884-{[3′-(azetidin-1-ylmethyl)-5- 572 [MH]+(trifluoromethyl)biphenyl-2-yl]oxy}-3- cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 989 4-{2-[1-(1-acetylazetidin-3-yl)-1H- 566[M³⁵ClH]+ pyrazol-5-yl]-4-fluorophenoxy}-5-chloro-2-fluoro-N-1,3-thiazol-4- ylbenzenesulfonamide 9904-(4-chloro-2-isoxazol-3-ylphenoxy)-N-(5- 493 [M³⁵ClH]+chloro-1,3-thiazol-2-yl)-3- cyanobenzenesulfonamide 9914-[2-(6-aminopyridin-2-yl)-4- 502 [M³⁵ClH]+fluorophenoxy]-N-(5-chloro-1,3-thiazol-2- yl)-3-cyanobenzenesulfonamide992 N-(5-chloro-1,3-thiazol-2-yl)-3-cyano-4- 476 [M³⁵ClH]+[5-fluoro-2-(1H-pyrazol-5- yl)phenoxy]benzenesulfonamide 993 tert-butyl4-(5-chloro-2-{2-cyano-4- 476 [M − Boc + H]+,[(1,2,4-thiadiazol-5-ylamino)sul- 574 [MH]−fonyl]phenoxy}phenyl)piperidine-1- carboxylate 9943-cyano-4-[4-(4-cyano-1H-pyrazol-1- 449 [MH]+yl)phenoxy]-N-1,3-thiazol-2- ylbenzenesulfonamide 995 methyl3-(5-chloro-2-{2-cyano-4-[(1,3- 505 [M³⁵ClH]+thiazol-2-ylamino)sulfonyl]phenoxy}phen- yl)azetidine-1-carboxylate 996ethyl 1-(4-{2-cyano-4-[(1,3-thiazol-2- 496 [MH]+ylamino)sulfonyl]phenoxy}phenyl)-1H- pyrazole-4-carboxylate 997tert-butyl 4-[5-chloro-2-(2,5-difluoro-4- 487 [M − Boc³⁵ClH]+{[(5-fluoro-1,3-thiazol-2-yl)amino]sul-fonyl}phenoxy)phenyl]-1H-pyrazole-1- carboxylate 998 tert-butyl4-(5-chloro-2-{2,5-difluoro-4- 469 [M − Boc³⁵ClH]+ [(1,3-thiazol-2-ylamino)sulfonyl]phenoxy}phenyl)-1H- pyrazole-1-carboxylate 9995′-chloro-2′-{2-cyano-4-[(1,2,4-thiadiazol- 513 [M³⁵ClH]+5-ylamino)sulfonyl]phenoxy}biphenyl-4- carboxylic acid 1000(5′-chloro-2′-{2-cyano-4-[(1,2,4- 527 [M³⁵ClH]+ thiadiazol-5-ylamino)sulfonyl]phenoxy}biphenyl-3- yl)acetic acid 1001(5′-chloro-2′-{2-cyano-4-[(1,2,4- 527 [M³⁵ClH]+ thiadiazol-5-ylamino)sulfonyl]phenoxy}biphenyl-4- yl)acetic acid 10025′-chloro-2′-{2-cyano-4-[(1,2,4-thiadiazol- 513 [M³⁵ClH]+5-ylamino)sulfonyl]phenoxy}biphenyl-3- carboxylic acid 1003 methyl5′-chloro-2′-{2-cyano-4-[(1,2,4- 527 [M³⁵ClH]+ thiadiazol-5-ylamino)sulfonyl]phenoxy}biphenyl-3- carboxylate 10043-cyano-4-(2-cyclopropyl-4- 428 [MH]+fluorophenoxy)-N-(5-fluoropyridin-2- yl)benzenesulfonamide 10053-cyano-N-(5-fluoropyridin-2-yl)-4-[2- 454 [MH]+ (tetrahydro-2H-pyran-2-yl)phenoxy]benzenesulfonamide 10063-cyano-4-{[6-(3-methoxyphenyl)pyridin- 465 [MH]+3-yl]oxy}-N-1,3-thiazol-2- ylbenzenesulfonamide 10074-(biphenyl-2-yloxy)-3-cyano-N-2- 433 [MH]+ thienylbenzenesulfonamide1008 2-{2-cyano-4-[(1,2,4-thiadiazol-5- 506 [MH]+ylamino)sulfonyl]phenoxy}-N,N- dimethylbiphenyl-3-carboxamide 10094-[4-chloro-2-(2-methylpyridin-3- 484 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 10104-[4-chloro-2-(3-methylpyrazin-2- 485 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 10114-[4-chloro-2-(3-methylpyridin-4- 484 [M³⁵ClH]+yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 10125-chloro-4-{4-chloro-2-[1-(1- 549 [M³⁵ClH]+methylazetidin-3-yl)-1H-pyrazol-5- yl]phenoxy}-2-fluoro-N-pyrimidin-2-ylbenzenesulfonamide 1013 4-[2-(2-aminopyridin-4-yl)-4- 522 [M³⁵ClH]+(trifluoromethyl)phenoxy]-3-chloro-N- pyrimidin-4-ylbenzenesulfonamide1014 4-[2-(2-aminopyridin-4-yl)-4- 488 [M³⁵ClH]+chlorophenoxy]-3-chloro-N-pyridazin-3- ylbenzenesulfonamide 1015 ethyl{5-[2-{2-cyano-4-[(1,2,4-thiadiazol- 579 [MH]+5-ylamino)sulfonyl]phenoxy}-5- (trifluoromethyl)phenyl]-1H-pyrazol-1-yl}acetate 1016 {5-[2-{2-cyano-4-[(1,2,4-thiadiazol-5- 551 [MH]+ylamino)sulfonyl]phenoxy}-5-(trifluoro-methyl)phenyl]-1H-pyrazol-1-yl}acetic acid 10175-chloro-2-fluoro-4-{2-[1-(1-methyl- 605 [M³⁵ClH]+azetidin-3-yl)-1H-pyrazol-5-yl]-4- (trifluoromethoxy)phenoxy}-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide 10184-(4-chloro-2-pyridazin-4-ylphenoxy)-N- 514 [M³⁵ClH]+1,3,4-thiadiazol-2-yl-3- (trifluoromethyl)benzenesulfonamide 10194-[2-(3-amino-1H-pyrazol-4-yl)-4- 495 [MH]+chlorophenoxy]-5-chloro-2-fluoro-N- pyrimidin-2-ylbenzenesulfonamide1020 4-[2-(2-aminopyridin-4-yl)-4- 495 [M³⁵ClH]+dchlorophenoxy]-2,5-ifluoro-N-1,3- thiazol-4-ylbenzenesulfonamide 10215-chloro-4-[4-(1-cyano-1-methylethyl)-2- 531 [M³⁵ClH]+pyridazin-4-ylphenoxy]-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide

Example 8783-cyano-4-[2-pyridazin-4-yl-4-(trifluoromethoxy)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

Example 878 from above can be prepared as follows.

2-pyridazin-4-yl-4-(trifluoromethoxy)phenol (Preparation 888, 1.03 g,4.02 mmol) was taken up in dimethyl sulfoxide (50 mL, 600 mmol) andpotassium carbonate (1.03 g, 7.45 mmol) added, followed by3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(Preparation 68, 1.74 g, 4.00 mmol). The reaction mixture was stirred at23° C. for 18 hours. The reaction mixture was diluted with water andextracted two times with ethyl ether. The combined organic phase waswashed successively with water and brine. The organic phase was driedover magnesium sulfate, then treated with activated carbon and filteredthrough a pad of diatomaceous earth. The solvent was removed in vacuo.The residue was dissolved in methylene chloride (100 mL, 2000 mmol) andtrifluoroacetic acid (2.0 mL, 26 mmol) was added. The solution wasstirred for 2 hours then concentrated in vacuo. The residue was purifiedby column chromatography (40 g silica gel column, 0 to 10% methanol indichloromethane gradient elution). The product fractions were combinedand concentrated in vacuo to a residue. The residue was triturated withethyl ether and the solid collected by filtration. Vacuum drying gave1.35 g of product as a white solid.

LCMS Rt=1.67 min, MS m/z 521 [MH]+

¹HNMR (300 MHz, d₆-DMSO): δ 7.14 (d, 1H), 7.57 (d, 1H), 7.68 (m, 1H),7.85 (dd, 1H), 7.89 (d, 1H), 7.98 (dd, 1H), 8.25 (d, 1H), 8.49 (s, 1H),9.29 (dd, 1H), 9.40 (dd, 1H).

Example 10224-{4-Chloro-2-[2-(dimethylamino)pyridin-4-yl]phenoxy}-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

A solution of lithium hexamethyldisilazide (1.0 M in tetrahydrofuran,272 uL, 0.272 mmol) was added to a solution of tert-butyl4-(4-(5-chloro-2-hydroxyphenyl)pyridin-2-yl)piperazine-1-carboxylate(Preparation 853, 100.0 mg, 0.2180 mmol) in N,N-dimethylformamide (3 mL,40 mmol). After stirring 5 minutes, tert-butyl[(2,4,5-trifluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation854, 72 mg, 0.18 mmol) was added as a solid. The reaction mixture wasstirred at ambient temperature. After 2 hours, the reaction mixture wasdiluted with water, neutralized with saturated aqueous ammoniumchloride, and extracted with ethyl acetate (3×). The combined organiclayers were washed with brine, dried over sodium sulfate, filtered, andconcentrated onto diatomaceous earth. The residue was purified byautomated flash chromatography (24 g SiO2, hexanes to ethyl acetate) toafford the intermediate.

LC/MS Rt=1.96 minutes, MS m/z 764 [M³⁵ClH]+

¹H NMR (d₆-DMSO): δ 9.11 (d, 1H), 8.10 (d, 1H), 7.98 (m, 1H), 7.91 (d,1H), 7.72 (d, 1H), 7.62 (m, 1H), 7.40 (d, 1H), 7.12 (m, 1H), 6.93 (br s,1H), 6.76 (m, 1H), 3.48 (m, 4H), 3.40 (m, 4H), 1.41 (s, 9H), 1.22 (s,9H).

Trifluoroacetic acid (500 μL, 7 mmol) was added to a solution oftert-butyl4-{4-[2-(4-{[(tert-butoxycarbonyl)(1,3-thiazol-4-yl)amino]sulfonyl}-2,5-difluorophenoxy)-5-chlorophenyl]pyridin-2-yl}piperazine-1-carboxylatein 5 mL of methylene chloride. After stirring 3 hours at ambienttemperature, the reaction mixture was concentrated in vacuo. The residuewas taken up in 2 mL of dimethyl sulfoxide, filtered through a plug ofcotton, and purified by reverse-phase HPLC. The product-containingfractions were concentrated in vacuo, and the residual solution wasdiluted with water and lyophilized to afford an off white powder (85.0mg, 83%).

LC/MS Rt=1.43 minutes, MS m/z 564 [M³⁵ClH]+

¹H NMR (d₆-DMSO): δ 11.42 (s, 1H), 8.91 (d, 1H), 8.13 (d, 1H), 7.75 (m,1H), 7.68 (d, 1H), 7.57 (m, 1H), 7.31 (d, 1H), 7.13 (m, 1H), 7.06 (d,1H), 7.01 (br s, 1H), 6.82 (m, 1H), 3.72 (m, 4H), 3.18 (m, 4H).

Example 10232,5-Difluoro-4-{2-[1-(1-methylazetidin-3-yl)-1H-pyrazol-5-yl]-4-(trifluoromethyl)phenoxy}-N-1,3-thiazol-4-ylbenzenesulfonamide

2-[1-(1-Methylazetidin-3-yl)-1H-pyrazol-5-yl]-4-(trifluoromethyl)phenol,(Preparation 855, 137 mg, 0.00046 mol) was dissolved in acetonitrile (10mL) and treated with potassium tert-butoxide (57 mg, 0.0005 mol) andstirred under nitrogen for 30 minutes. Tert-butyl1,3-thiazol-4-yl[(2,4,5-trifluorophenyl)sulfonyl]carbamate, (Preparation297, 182 mg, 0.00046 mol) was added and the solution stirred for 2hours. Water (0.2 mL) was added and the solution evaporated. The residuewas suspended in water and extracted with ethyl acetate (1×20 mL). Theorganic layer was separated and washed with brine (2×20 mL). The organiclayer was separated, dried over anhydrous sodium sulphate, filtered andevaporated to give a foam. The foam was purified using an ISCO™Companion (4 g. silica gel, eluting with dichloromethane:acetic acid99.5:0.5 to dichloromethane:methanol:acetic acid 95:5:0.5). Theappropriate fractions were evaporated to give a film. The film wastriturated with diethyl ether to give the title compound as a whitesolid (11 mg).

LCMS Rt=1.19 minutes, MS m/z=572 [MH]+

TLC dichloromethane:methanol:acetic acid 95:5:0.5, Rf=0.5

¹HNMR (CDCl₃) δ 3.15 (s, 3H) 4.24-4.34 (m, 2H) 4.83-4.87 (m, 2H)5.41-5.49 (m, 1H) 6.42 (s, 1H) 6.47 (s, 1H) 6.82 (d, 1H) 7.27 (s, 1H)7.61 (d, 1H) 7.67 (s, 1H) 7.77 (s, 1H) 7.91-7.95 (m, 1H) 8.21 (s, 1H).

Example 10244-{4-Chloro-2-[1-(1-ethylazetidin-3-yl)-1H-pyrazol-5-yl]phenoxy}-3-cyano-N-1,3-thiazol-4-ylbenzenesulfonamide

To a suspension of4-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy]-3-cyano-N-1,3-thiazol-4-ylbenzenesulfonamide,Example 809 (500 mg, 0.000797 mol) in methanol (4 mL) anddichloromethane (4 mL) was added triethylamine (161 mg, 0.00159 mol) andthe reaction cooled to 0° C. in an ice/water bath. To the suspension wasadded sodium triacetoxyborohydride (422 mg, 0.00199 mol) and thereaction was then stirred at 0° C. for 10 minutes. Acetaldehyde (105 mg,0.00239 mol) was added dropwise and the reaction stirred at 0° C. for1.5 hours. The solvent was removed in vacuo to give an orange oil whichwas partitioned between dichloromethane (25 mL) and water (25 mL). Theorganic layer was separated and the aqueous layer was extracted withdichloromethane (2×20 mL). The combined organic layers were washed withsaturated aqueous sodium chloride solution (20 mL) and filtered througha phase separator. The solvent was removed in vacuo to give a pink solidwhich was triturated in hot ethyl acetate (10.0 mL), allowed to cool toroom temperature and then filtered to give the title compound as a whitesolid, (431 mg).

LCMS Rt=1.95 minutes, MS m/z=541 [MH]+

¹HNMR (d₆-DMSO) δ 1.11 (t, 3H), 3.26 (q, 2H), 4.16 (brs, 2H), 4.42(brs., 2H), 5.14 (brs., 1H), 6.30 (d, 1H), 6.99 (d, 1H), 7.11 (d, 1H),7.53 (d, 1H), 7.63 (d, 1H), 7.72-7.77 (m, 2H), 7.89 (dd, 1H), 8.14 (d,1H), 8.92 (d, 1H).

Example 10254-{4-Chloro-2-[2-(cyclobutyloxy)pyridin-4-yl]phenoxy}-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

4-{4-chloro-2-[2-(cyclobutyloxy)pyridin-4-yl]phenoxy}-3-cyano-N-(2,4-dimethoxybenzyl)-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide,(Preparation 861, 40 mg, 0.000058 mol) was dissolved in dichloromethane(1 mL) and cooled to 0° C. Trifluoroacetic acid (0.2 mL, 0.00261 mol)was added and the reaction stirred for 1 hour warming slowly to roomtemperature. The solvent was removed in vacuo and the residueredissolved in dichloromethane (1 mL). Once again the solvent wasremoved in vacuo to give a purple residue (154 mg). The material wassuspended in methanol (3 mL) and filtered through Celite™. The solventwas removed in vacuo to obtain the title compound as an off white solid(15.5 mg).

LCMS Rt=1.83 minutes, MS m/z=540 [M³⁵ClH]+

¹HNMR (CD₃OD) δ 1.62-1.74 (m, 1H), 1.79-1.88 (m, 1H), 2.04-2.14 (m, 2H),2.38-2.45 (m, 2H), 5.03-5.11 (m, 1H), 6.87-6.90 (m, 2H), 7.08-7.09 (m,1H), 7.33 (d, 1H), 7.57-7.60 (dd, 1H), 7.63 (d, 1H), 7.93 (dd, 1H),8.07-8.09 (m, 1H), 8.12 (d, 1H), 8.20 (s, 1H).

Example 10264-{4-Chloro-2-[2-(dimethylamino)pyridin-4-yl]phenoxy}-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

3-Cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(Preparation 65, 40 mg, 0.14 mmol),4-chloro-2-[2-(dimethylamino)pyridin-4-yl]phenol (Preparation 865, 35.0mg, 0.141 mmol) and potassium carbonate (58 mg, 0.42 mmol) in dimethylsulfoxide (1 mL, 20 mmol) was stirred at 150° C. for 16 hours. Thereaction mixture was cooled to ambient temperature and poured intosaturated aqueous ammonium chloride. The aqueous layer was extractedwith ethyl acetate (3×). The combined organic layers were washed withbrine, dried over sodium sulfate, filtered, and concentrated in vacuo.The residue was taken up in methylene chloride, concentrated ontodiatomaceous earth, and purified by automated flash chromatography (12 gSiO₂, hexanes to 20% methanol in ethyl acetate). The product-containingfractions were concentrated in vacuo then lyophilized from water andminimal acetonitrile to afford the product as a light yellow powder (40mg, 60%).

LC/MS Rt=1.40 minutes, MS m/z 513 [M³⁵ClH]+

¹H NMR (d₆-DMSO): δ 8.03 (m, 2H), 7.94 (s, 1H), 7.86 (m, 1H), 7.68 (d,1H), 7.60 (m, 1H), 7.41 (d, 1H), 6.89 (d, 1H), 6.60 (m, 2H), 2.95 (s,6H).

Example 10275-Chloro-2-fluoro-4-[2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide

To a stirred solution of5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-[2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide(Preparation 900, 30.3 g, 44.4 mmol) in 1,4-dioxane (250 mL) at roomtemperature was added a 4M solution of HCl in 1,4-dioxane (300 mL)dropwise over 30 minutes. The resulting suspension was left to stir atroom temperature for 3 hours before concentration in vacuo. The residuewas azeotroped with diethyl ether (3×300 mL) followed by a diethyl ethertrituration (200 mL) to provide crude material as a fawn coloured solid.This material was suspended in methanol (200 mL) and filtered throughCelite, washed with methanol (400 mL) and the resulting filtrateconcentrated in vacuo to give a sand coloured solid. This material wassuspended in water (100 mL) and treated with 880 ammonia (60 mL)portionwise until pH 9-10 was achieved. The resulting solution waswashed with diethyl ether (3×75 mL) and the aqueous layer acidified topH=5 with citric acid. The mixture was then extracted with ethyl acetate(3×200 mL) and brine (100 mL) added to aid separation. The combinedorganic layers were washed with water (200 mL), dried over MgSO₄ andconcentrated in vacuo to approximately 100 mL whereby a precipiatate wasobserved. This mixture was allowed to cool for 18 hours and theresulting solid filtered and washed with cold ethyl acetate (10 mL) anddried in vacuo at 60° C. to provide the title compound as a sandcoloured crystalline solid (17.5 g) containing 8.2% by weight ethylacetate solvate.

LCMS Rt=1.58 minutes. MS m/z 532 [M³⁵ClH]+

¹HNMR (d₆-DMSO): δ 7.30 (d, 1H), 7.50 (d, 1H), 7.83-7.85 (m, 1H),7.92-7.98 (m, 2H), 8.08-8.13 (m, 1H), 8.81 (s, 1H), 9.32 (d, 1H), 9.51(s, 1H).

Microanalysis: C₁₉H₁₀ClF₄N₅O₃S₂. 0.55 EtOAc required C, 43.91, H, 2.48;N, 12.08; Cl, 6.13%. Found C, 43.90; H, 2.42; N, 12.04; Cl, 6.14%.

Example 10284-[2-(3-amino-1H-pyrazol-4-yl)-4-(trifluoromethyl)phenoxy]-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide

To a solution of5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethyl)phenoxy}-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide(Preparation 867, 3.20 g, 4.00 mmol) in ethanol (200 mL) was addedsaturated aqueous ammonium chloride solution (50 mL) and iron (5.66 g,101 mmol). The reaction solution was heated at 80° C. for 15 minutes.The solution was cooled, filtered and adjusted to pH=9 with saturatedaqueous sodium bicarbonate solution. The mixture was filtered and thenconcentrated to remove most of the ethanol. The resulting slurry wasextracted with dichloromethane (3×). The organic extracts were combined,dried over anhydrous magnesium sulfate, filtered, and concentrated. Thisprovided the aminopyrazole as a yellow foam. To this was added an HCl(g) saturated methanol solution (200 mL) and the mixture heated at 60°C. for two hours. The reaction solution was cooled, concentrated, andpurified by automated flash column chromatography using a 0-10%methanol/dichloromethane gradient. Additional purification by prep HPLCprovided the TFA salt. The resulting white solid was redissolved in aHCl (g) saturated methanol solution and concentrated (3×) in order toisolate the HCl salt of the title compound (1.20 g, 53%) as a whitesolid.

LC/MS Rt=1.67 minutes

MS m/z 535 [M³⁵ClH]+

¹H NMR (d₆-DMSO): δ 7.25 (d, 1H), 7.32 (d, 1H), 7.73 (m, 1H), 7.96 (d,1H), 7.99 (m, 1H), 8.09 (s, 1H), 8.86 (s, 1H).

Example 10294-[2-(3-amino-1H-pyrazol-4-yl)-4-(trifluoromethyl)phenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide

To a solution of tert-butyl[(5-chloro-2-fluoro-4-{2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethyl)phenoxy}phenyl)sulfonyl]1,3-thiazol-4-ylcarbamate(Preparation 872, 55 g, 74 mmol) in ethanol (800 mL) was added saturatedaqueous ammonium chloride solution (200 mL, 3000 mmol) and iron (65 g,1200 mmol). The reaction solution was heated at 80° C. for two hours atwhich point iron (10 g, 185 mmol) was added and the mixture heated foran additional hour. The solution was cooled, filtered and adjusted topH=9 with saturated aqueous sodium bicarbonate solution. The mixture wasfiltered and then concentrated to remove most of the ethanol. Theresulting slurry was extracted with dichloromethane (4×). The organicextracts were combined, dried over anhydrous magnesium sulfate,filtered, and concentrated to provide the free amine as an orange oil.Purification by manual flash column chromatography using 40% then 75%ethyl acetate/hexanes and a 5×31 cm column provided a mix of Bocprotected sulphonamide and non-Boc protected sulphonamide free amine asan orange oil. To this mixture was added an HCl (g) saturated methanolsolution (400 mL) and the mixture heated at 60° C. for 7 hours. Thereaction solution was cooled and concentrated to give a white solid. Thesolid was redissolved in methanol, heated to reflux and ethyl acetateadded until just before a precipitate formed. It was then cooled, washedwith ethyl acetate and dichloromethane to provide the title compound asa white solid. This was repeated until no more clean product wasobtained. The impure filtrate was purified by prep HPLC, the productfractions concentrated and the TFA salt exchanged for an HCl salt. Allproduct was combined, dissolved in methanol, filtered, concentrated andisolated as a white solid with 1.5 eq of HCl present (30.3 g, 70%) viatrituration with dichloromethane.

LC/MS Rt=1.73 minutes MS m/z 534 [M³⁵ClH]+

¹H NMR (d₆-DMSO): δ 7.00 (d, 1H), 7.10 (d, 1H), 7.30 (m, 1H), 7.53 (m,1H), 7.61 (m, 1H), 7.93 (d, 1H), 7.97 (s, 1H), 8.91 (d, 1H).

Example 10304-[4-Chloro-2-(2-piperazin-1-ylpyrimidin-4-yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

3-Cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(Preparation 65, 43.6 mg, 0.154 mmol), tert-butyl4-[4-(5-chloro-2-hydroxyphenyl)pyrimidin-2-yl]piperazine-1-carboxylate(Preparation 873, 50.0 mg, 0.128 mmol) and potassium carbonate (53 mg,0.38 mmol) in dimethyl sulfoxide (1 mL, 10 mmol) was stirred at 100° C.for 16 hours. The reaction mixture was cooled to ambient temperature andpoured into saturated aqueous ammonium chloride. The aqueous layer wasextracted with ethyl acetate (3×). The combined organic layers werewashed with brine, dried over sodium sulfate, filtered, and concentratedin vacuo to afford the crude intermediate, tert-butyl4-[4-(5-chloro-2-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}phenyl)pyrimidin-2-yl]piperazine-1-carboxylate,as a yellow solid. Trifluoroacetic acid (300 uL, 4 mmol) was added to asolution of tert-butyl4-[4-(5-chloro-2-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}phenyl)pyrimidin-2-yl]piperazine-1-carboxylate(83 mg, 0.154 mmol) in methylene chloride (2.9 mL, 46 mmol). After 1hour, the reaction mixture was concentrated in vacuo. The residue waspurified by reverse-phase HPLC to afford the product as a white solid(trifluoroacetic acid salt, 36 mg, 51%).

LC/MS Rt=1.52 minutes, MS m/z 555 [M³⁵ClH]+

¹H NMR (d₆-DMSO): δ 8.49 (d, 1H), 8.38 (s, 1H), 8.23 (d, 1H), 7.97 (m,2H), 7.72 (m, 1H), 7.49 (d, 1H), 7.04 (d, 1H), 6.99 (d, 1H), 3.73 (m,4H), 3.08 (m, 4H).

Example 10314-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-pyridazin-3-ylbenzenesulfonamide

4-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-(methoxymethyl)-N-pyridazin-3-ylbenzenesulfonamideand4-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-[(3E)-2-(methoxymethyl)pyridazin-3(2H)-ylidene]benzenesulfonamide,(Preparation 875, 93 mg, 0.17 mmol) in trifluoroacetic acid (1 mL, 10mmol) was stirred for 24 hours. The reaction mixture was concentratedand the residue was taken in methanol (1 mL, 20 mmol) and 2 M ofhydrogen chloride in water (1 mL, 2 mmol). After stirring for two days,the reaction mixture was concentrated and the residue liophilized fromacetonitrile-water to give 76 mg of product as a hydrochloride salt.

LCMS Rt=1.36 min MS m/z 506 [MH]+

¹H NMR (300 MHz, d₆-DMSO): δ 6.99 (dd, 1H), 7.12 (d, 1H), 7.21 (d, 1H),7.24 (s, 1H), 7.62 (dd, 1H), 7.73 (d, 1H), 7.78 (dd, 1H), 7.96-8.02 (m,3H), 8.17 (bs, 2H), 8.40 (dd, 1H), 13.8 (bs, 1H).

Example 10324-{2-[2-(Azetidin-1-ylmethyl)pyridin-4-yl]-4-chlorophenoxy}-2,5-difluoro-N-1,3-thiazol-4-ylbenzenesulfonamide

tert-Butyl[(4-{2-[2-(azetidin-1-ylmethyl)pyridin-4-yl]-4-chlorophenoxy}-2,5-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate,(Preparation 878, 0.325 g, 0.0005 mol) was dissolved in dichloromethane(3 mL) then 4 molar hydrogen chloride in 1,4-dioxane (3 mL) was added.The reaction was stirred at room temperature for 18 hours. The reactionwas concentrated in vacuo and the crude product purified by preparativeHPLC to give the title compound.

LCMS Rt=1.07 minutes, MS m/z=549 [M³⁵ClH]+

Example 10333-Cyano-4-{2-[1-(1-ethylazetidin-3-yl)-1H-pyrazol-5-yl]-4-(trifluoromethyl)phenoxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

4-[2-(1-Azetidin-3-yl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide,(Preparation 881, 2.90 g, 0.00529 mol) was dissolved in acetic acid (6mL) with warming and then dichloromethane (50 ml) was added. Thesolution was stirred under nitrogen and cooled in an ice/acetone bath.Sodium triacetoxyborohydride (5.0 g, 0.0236 mol) was added, stirred withcooling for 15 minutes and then a solution of acetaldehyde (1.2 mL,0.021 mol) in dichloromethane (10 mL) was added dropwise over 45minutes. The reaction mixture was stirred with cooling for 1 hour andthen allowed to warm to room temperature and stirred for a further 45minutes. LCMS indicated that a small amount of starting materialremained so the mixture was cooled again in ice and a further portion ofsodium triacetoxyborohydride (0.50 g, 0.00236 mol) was added, followedby acetaldehyde (0.10 mL, 0.00178 mol). The reaction mixture was stirredwhilst warming to room temperature over 1 hour. Water (5.0 mL) was addedto quench the reaction and the mixture was stirred at room temperaturefor 15 minutes and the solvents were then removed in vacuo. The residuewas partitioned between ethyl acetate (150 mL) and water (50 mL) with0.880 aqueous ammonia (20 mL) added. The organic layer was washed withwater (2×50 mL), dried over anhydrous sodium sulphate, filtered and thesolvents removed in vacuo to give the crude product as a pale yellowfoam (2.30 g). A further batch was obtained by re-extracting thecombined aquous layers with ethyl acetate (80 mL) to give a pale yellowfoam (700 mg). The two batches were combined and re-crystallized fromethyl acetate (25 mL) to give the title compound as a white powder (1.84g). 300 mg of this material was re-crystallized from water/ethanol togive the pure title compound (215 mg).

LCMS Rt=11.40 minutes, MS m/z=576 [MH]+

¹HNMR (d₆-DMSO) δ 1.09 (t, 3H), 3.32 (brm, 2H), 4.23-4.49 (brm, 4H),5.13 (m, 1H), 6.47 (s, 1H), 7.05 (d, 1H), 7.53 (d, 1H), 7.73 (s, 1H),7.88-8.00 (m, 4H), 8.04 (d, 1H).

The remaining material (1.53 g, 0.00266 mol) was added to a solutionsodium hydroxide (97 mg, 0.00243 mol) in water (15 mL) and warmed togive a slightly cloudy solution which was filtered whilst still hot andthe water was then removed in vacuo to give a gum. The gum was treatedwith tert-butylmethylether (50 mL) for 3 days and then the solvent wasremoved in vacuo to give the sodium salt of the title compound as a foam(1.20 g).

LCMS Rt=1.28 minutes, MS m/z=576 [MH]+

¹HNMR (d₆-DMSO) δ 0.85 (t, 3H), 2.41 (q, 2H), 3.24 (m, 2H), 3.52 (m,2H), 4.74 (m, 1H), 6.33 (s, 1H), 7.07 (d, 1H), 7.48-7.56 (m, 2H),7.81-8.03 (m, 5H).

Example 10345-Chloro-2-fluoro-4-[5-fluoro-2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide

5-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide(Preparation 247, 63 mg, 0.14 mmol) was added to a mixture of5-fluoro-2-pyridazin-4-yl-4-(trifluoromethyl)phenol (Preparation 884,mg, 0.14 mmol) and potassium carbonate (22 mg, 0.16 mmol) in dimethylsulfoxide (2 mL, 30 mmol). The reaction mixture was stirred at ambienttemperature. After 3 hours the reaction mixture was diluted with waterand saturated aqueous ammonium chloride and extracted with ethyl acetate(3×). The combined organic layers were washed with water then brine,dried over sodium sulfate, filtered, and concentrated in vacuo. Theresidue was taken up in methylene chloride, concentrated ontodiatomaceous earth, and purified by automated flash chromatography (12 gSiO₂, hexanes to ethyl acetate) to afford the intermediate5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-[5-fluoro-2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamideas a glass (22 mg, 23%).

LC/MS Rt=1.88 minutes, MS m/z 700 [M³⁵ClH]+

Trifluoroacetic acid (500 uL, 6 mmol) was added to a solution of5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-[5-fluoro-2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide(22 mg) in methylene chloride (5 mL, 70 mmol). After stirring 20 min,the reaction mixture was concentrated onto diatomaceous earth andpurified by automated flash chromatography (4 g SiO2, methylene chlorideto 9:1 methylene chloride-methanol) to afford the product as a tan solid(6 mg, 9%).

LC/MS Rt=1.72 minutes, MS m/z 550 [M³⁵ClH]+

¹H NMR (d₆-DMSO): δ 9.50 (m, 1H), 9.33 (m, 1H), 8.83 (s, 1H), 8.16 (d,1H), 7.95 (m, 2H), 7.62 (d, 1H), 7.52 (d, 1H).

Example 10353-Cyano-4-[5-fluoro-2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiodiazol-5-ylbenzenesulfonamide

3-Cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(Preparation 68, 59 mg, 0.14 mmol) was added to a mixture of5-fluoro-2-pyridazin-4-yl-4-(trifluoromethyl)phenol (Preparation 884,mg, 0.14 mmol) and potassium carbonate (22 mg, 0.16 mmol) in dimethylsulfoxide (2 mL, 30 mmol). The reaction mixture was stirred at ambienttemperature. After 3 hours the reaction mixture was diluted with waterand saturated aqueous ammonium chloride and extracted with ethyl acetate(3×). The combined organic layers were washed with water then brine,dried over sodium sulfate, filtered, and concentrated in vacuo. Theresidue was taken up in methylene chloride, concentrated ontodiatomaceous earth, and purified by automated flash chromatography (12 gSiO2, hexanes to ethyl acetate) to afford the intermediate as a glass(63 mg, 69%).

LC/MS Rt=1.88 minutes, MS m/z 673 [MH]+

Trifluoroacetic acid (500 uL, 6 mmol) was added to a solution of3-cyano-N-(2,4-dimethoxybenzyl)-4-[5-fluoro-2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(63 mg) in methylene chloride (5 mL, 70 mmol). After stirring 20minutes, the reaction mixture was concentrated onto diatomaceous earthand purified by automated flash chromatography (12 g SiO2, methylenechloride to 9:1 methylene chloride-methanol) to afford the product as alight yellow solid (38 mg, 54%).

LC/MS Rt=1.66 minutes, MS m/z 523 [MH]+

¹H NMR (d₆-DMSO): δ 9.45 (m, 1H), 9.31 (m, 1H), 8.48 (s, 1H), 8.30 (d,1H), 8.23 (d, 1H), 8.04 (m, 1H), 7.90 (m, 1H), 7.75 (d, 1H), 7.44 (d,1H).

Example 10364-[2-(3-amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-pyrimidin-4-ylbenzenesulfonamide

4-{2-[3-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-chlorophenoxy}-5-chloro-2-fluoro-N-(methoxymethyl)-N-pyrimidin-4-ylbenzenesulfonamide(Preparation 887, 58 mg, 0.093 mmol) in methanol (1 mL, 20 mmol) and 2 Mof hydrogen chloride in water (1 mL, 2 mmol) was heated at 60° C. for 2hours then concentrated. The residue was liophilized fromacetonitrile-water to give 50 mg of a white solid.

LCMS Rt=1.64 min, MS m/z 495 [MH]+

¹HNMR (d₆-DMSO): δ 6.93 (m, 2H), 7.18 (d, 1H), 7.46 (dd, 1H), 7.72 (d,1H), 7.97 (m, 2H), 8.21 (d, 1H), 8.58 (s, 1H).

Example 10372-fluoro-5-methyl-4-[2-pyridazin-4-yl-4-(trifluoromethoxy)phenoxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide

2-pyridazin-4-yl-4-(trifluoromethoxy)phenol (Preparation 888, 30 mg,0.12 mmol) was taken up in dimethyl sulfoxide (1 mL, 20 mmol) andpotassium carbonate (30 mg, 0.22 mmol) added, followed byN-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide(Preparation 889, 51.7 mg, 0.117 mmol). The reaction was heated at 60°C. for 72 hours. The reaction was cooled and diluted with 1N HCl. Theresulting precipitate was collected by filtration. The solid wasdissolved in methylene chloride (1.0 mL, 16 mmol) and dried overmagneisum sulfate. The solution was then treated with trifluoroaceticacid (45 uL, 0.58 mmol) and stirred for 2 hours. The reaction mixturewas concentrated in vacuo. The residue was purified by reverse phaseHPLC. Product fractions were combined and the solvent removed in vacuoto give a residue. The product was purified a second time by columnchromatography (4 g silica gel column, 0 to 10% methanol in methylenechloride gradient elution). Product fractions were combined andconcentrated in vacuo to give 11.2 mg of colorless glass.

LCMS Rt=1.67 min, MS m/z 528 [MH]+

¹HNMR (300 MHz, d₆-DMSO): δ 2.20 (s, 3H), 6.94 (d, 1H), 7.23 (d, 1H),7.54 (m, 1H), 7.75 (d, 1H), 7.81 (d, 1H), 7.90 (dd, 1H), 8.78 (s, 1H),9.29 (dd, 1H), 9.45 (dd, 1H).

Example 10384-[2-(3-amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-pyridazin-3-ylbenzenesulfonamide

The title compound was prepared according to the procedure in Example1036 using4-{2-[3-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-chlorophenoxy}-5-chloro-2-fluoro-N-(methoxymethyl)-N-pyridazin-3-ylbenzenesulfonamideand4-{2-[3-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-chlorophenoxy}-5-chloro-2-fluoro-N-[(3E)-2-(methoxymethyl)pyridazin-3(2H)-ylidene]benzenesulfonamide(Preparation 891).

LCMS Rt=1.62 min, MS m/z 495 [MH]+

¹HNMR (d₆-DMSO): δ 6.94 (d, 1H), 7.17 (d, 1H), 7.44 (dd, 1H), 7.71 (d,1H), 7.76 (dd, 1H), 7.97 (m, 3H), 8.38 (dd, 1H).

Example 1039

[(2Z)-2-[({4-[4-Chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]-3-cyanophenyl}sulfonyl)imino]-1,3-thiazol-3(2H)-yl]methyldihydrogen phosphate

Di-tert-butyl[(2Z)-2-[({4-[4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]-3-cyanophenyl}sulfonyl)imino]-1,3-thiazol-3(2H)-yl]methylphosphate, (Example 1040, 250 mg, 0.00036 mol) was dissolved in ethylacetate (10 mL) and then trifluoroacetic acid (1 mL) was added. Thesolution was stirred at room temperature for 3 hours, then a furtherportion of trifluoroacetic acid (2 mL) was added and stirred at roomtemperature for 18 hours. The solvents were removed in vacuo and theresidue was partitioned between tert-butylmethyl ether (30 mL) and water(40 mL) and a few drops of aqueous sodium hydroxide solution (2 molar).The aqueous layer was then acidified to pH 1-2 with aqueous hydrochloricacid (2 molar) to give a sticky cream precipitate which was dissolved ina mixture of dichloromethane, ethanol and methanol. This organic layerwas dried over anhydrous sodium sulphate, filtered and the solventsremoved in vacuo to give the crude product which was triturated withethyl acetate to give the title compound as a buff powder, (85 mg).

MS m/z=582 [M³⁵ClH]+

¹HNMR (d₆-DMSO) δ 3.73 (s, 3H), 5.60 (d, 2H), 6.22 (d, 1H), 6.90-6.96(m, 2H), 7.34 (s, 1H), 7.41 (d, 1H), 7.47-7.51 (m, 1H), 7.66-7.71 (m,2H), 7.92-7.97 (m, 1H), 8.18 (d, 1H).

Example 1040 Di-tert-butyl[(2Z)-2-[({4-[4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]-3-cyanophenyl}sulfonyl)imino]-1,3-thiazol-3(2H)-yl]methylphosphate

4-[4-Chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]-3-cyano-N-1,3-thiazol-2-ylbenzenesulfonamide,(Example 170, 200 mg, 0.000424 mol), di-tert-butyl chloromethylphosphate (J. Med. Chem. 51 (2008) p 1111-1114, supplimentary data) (160mg, 0.000619 mol) and cesium carbonate (420 mg, 0.00129 mol) werestirred in dimethylformamide (2 mL) at 60° C. for 18 hours. The mixturewas cooled then partitioned between tert-butylmethyl ether (80 mL) andwater (40 mL), the organic layer was dried over anhydrous sodiumsulphate, filtered and the solvent removed in vacuo to give the titlecompound as a pale yellow gum, (250 mg).

LCMS=1.63 minutes, MS m/z=694 [M³⁵ClH]+

¹HNMR (CDCl₃) δ 1.42 (s, 9H), 1.51 (s, 9H), 3.87 (s, 3H), 5.68 (d, 2H),6.21 (s, 1H), 6.50 (d, 1H), 6.66 (d, 1H), 7.13 (d, 1H), 7.23 (d, 1H),7.39 (s, 1H), 7.46 (s, 1H), 7.48-7.53 (m, 1H), 7.94-7.99 (m, 1H), 8.15(s, 1H).

PREPARATIONS

The following Preparations illustrate the preparation of certainintermediates used to prepare the Examples above.

Preparation 14(2,4-dimethoxy-benzyl)-[1,2,4]thiadiazol-5-yl-amine/N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine

A mixture of 5-amino-1,2,4-thiadiazole (1 g; 9.89 mmol) and2,4-dimethoxybenzaldehyde (1.81 g; 10.9 mmol) in toluene (30 ml) wasrefluxed under Dean and Stark conditions for 2 hours. The reactionmixture was evaporated, the residue taken up in methanol (25 ml), NaBH₄(600 mg; 15.9 mmol) added carefully in small portions (vigorouseffervescence after each addition), and the reaction was left stirringovernight at ambient temperature. Aqueous HCl (2M, 1 ml) was addedfollowed by aqueous NaOH (2M, 10 ml). The bulk of the methanol wasevaporated, water (20 ml) added and extracted with ethyl acetate (2×30ml). The combined organic was washed brine (20 ml), dried, andevaporated. The residue was purified by silica gel column chromatography(ISCO™ column 120 g; ethyl acetate:heptane 25:75 to 60:40) to furnish asemi-solid residue that was re-evaporated from heptane. 2-3 ml tBuOMewas added, then 2-3 ml heptane, the solid filtered off, washed withheptane and dried to afford 1.22 g of the title compound.

¹HNMR (d₆-DMSO): δ 3.73 (s, 3H), 3.78 (s, 3H), 4.36 (d, J=5.46 Hz, 2H),6.47 (dd, J=8.58, 2.34 Hz, 1H), 6.56 (d, J=2.34 Hz, 1H), 7.15 (d, J=8.19Hz, 1H), 7.88 (s, 1H), 8.65 (br. S., 1H)

Preparation 37 4′-isopropoxy-2′-methylbiphenyl-2-ol

2-Iodophenol (1.54 g, 7.00 mmol) was combined with2-(4-isopropoxy-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(Preparation 38, 2.00 g, 7.24 mmol), cesium carbonate (4.56 g, 13.99mmol) and palladium tetrakis(triphenylphosphine) (0.24 g, 0.21 mmol) in1,2-dimethoxyethane (40 mL). The reaction mixture was heated to refluxfor 18 hours. The reaction mixture was cooled to room temperature andthen acidified with a 1 N aqueous HCl solution. The organics wereextracted 3 times with diethylether. The organic layers were combined,washed with brine, dried over magnesium sulphate and concentrated invacuo. The residue was purified by column chromatography using as eluanta mixture heptane/ethyl acetate to afford 543 mg (31% yield) of4′-isopropoxy-2′-methylbiphenyl-2-ol as a pale yellow oil. MS m/z 243[MH]+

¹HNMR (CDCl₃): δ 1.37 (d, 6H), 2.12 (s, 3H), 4.56-4.62 (m, 1H), 6.80(dd, 1H), 6.85 (d, 1H), 6.93-7.01 (m, 2H), 7.10-7.14 (m, 2H), 7.23-7.28(m, 1H).

Preparation 382-(4-isopropoxy-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

In a flame-dried flask under nitrogen,3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (seeWO2007092751A, 2.30 g, 9.82 mmol) was dissolved in dimethylformamide (40mL). Sodium hydride 60% dispersion in mineral oil (0.48 g, 12 mmol) wasadded to the mixture. The reaction mixture was stirred at roomtemperature under nitrogen for 30 minutes. 2-Iodopropane (2.55 g, 15.00mmol) was added and the reaction mixture was stirred at 70° C. for 18hours. The reaction mixture was quenched with water. The organics wereextracted 3 times with diethylether. The organic layers were combined,dried over magnesium sulphate and concentrated in vacuo. The residue waspurified by column chromatography, using as eluant a mixture ofheptane/ethyl acetate, to afford 2.02 g (73% yield) of2-(4-isopropoxy-2-methyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolaneas a yellow oil. MS m/z 277 [MH]+

¹HNMR (CDCl₃): 1-1.32 (m, 18H), 2.50 (s, 3H), 4.50-4.60 (m, 1H),6.67-6.69 (m, 2H), 7.69 (d, 1H).

Preparation 42 4-(4-fluorophenyl)-2-(methylamino)pyrimidin-5-ol

(2-Amino-1,3-oxazol-5-yl)(4-fluorophenyl)methanone (US2005032859, 1 g,4.85 mmol) and 40% methyl amine water in excess (50 mL) were combined intert-butanol (50 mL). The mixture was stirred at 50° C. under nitrogenfor 2 hours. The mixture was concentrated in vacuo. The residue wasfiltered through a pad of silica gel using neat ethyl acetate as eluant.The solution was concentrated in vacuo to afford 0.73 g (66%) of4-(4-fluorophenyl)-2-(methylamino)pyrimidin-5-ol as a crystalline brownsolid. MS m/z 220 [M]+

¹H NMR CDCl₃/CD₃OD: δ 2.94 (s, 3H), 6.90-7.20 (m, 2H), 7.95 (s, 1H),8.00-8.30 (m, 2H).

Preparation 444-(2-bromo-4-fluoro-phenoxy)-3-cyano-N-[1,2,4]thiadiazol-5-ylbenzenesulfonamide

Prepared according to the process of Preparation 51, using2-bromo-4-fluorophenol and3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(Preparation 65). LCMS Rt=3.01 min MS m/z 284 [MH]+ ¹HNMR (d₆-DMSO): δ6.8 (m, 1H), 7.4 (m, 1H), 7.6 (m, 1H), 7.8 (m, 1H), 8.0 (m, 1H), 8.3 (m,1H), 8.5 (s, 1H).

Preparation 46 3-cyano-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide

To 2-aminothiazole (12.55 g, 125.3 mmol) was added pyridine (46 ml) anddichloromethane (75 mL) and the mixture stirred to give a solution. Asolution of 3-cyano-4-fluorobenzenesulfonyl chloride (25 g, 114 mmol) indichloromethane (50 ml) was added over approx 20 minutes at roomtemperature. The reaction was stirred at this temperature for 2 daysbefore decanting the supernatant and concentrating in vacuo to furnish adark oil. 2M HCl (200 ml) was added and the mixture triturated untilsolidification occurred. A brick red solid was filtered off, washed withwater and dried to furnish 21.5 g of the title product. ¹HNMR (d₆-DMSO):δ 6.9 (d, 1H), 7.3 (m, 1H), 7.6 (m, 1H), 8.15 (m, 1H), 8.3 (d, 1H), 12.9(br s 1H). LCMS Rt=2.34 min MS m/z 284 [MH]+.

Preparation 503-cyano-4-(2-iodo-phenoxy)-N-[1,2,4]thiadiazol-5-yl-benzenesulfonamide

To a solution of 2-iodophenol (6.0 mmol, 1320 mg) and K₂CO₃ (10.5 mmol,1450 mg) in DMF (15.0 mL) was added3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(Preparation 65, 4.5 mmol, 1280 mg). The reaction mixture was heated at80° C. for 24 hours. The reaction was cooled to room temperature and themixture was poured into 1 N aqueous HCl (100 mL) to obtain a whitesolid. The afforded solid was washed with heptane and the solid wasdried in vacuo to furnish 1.932 g of the title compound. LCMS Rt=1.67minutes MS m/z 485 [MH]+

¹HNMR (d₆-DMSO): δ 6.78 (d, 1H), 7.14-7.22 (m, 1H), 7.39-7.44 (m, 1H),7.52-7.58 (m, 1H), 7.99-8.05 (m, 2H), 8.33 (d, 1H), 8.52 (s, 1H).

Preparation 513-cyano-4-(2-bromo-6-methyl-phenoxy)-N-[1,2,4]thiadiazol-5-yl-benzenesulfonamide

To a solution of 2-bromo-6-methylphenol (6.0 mmol, 1120 mg) and K₂CO₃(10.5 mmol, 1450 mg) in DMF (15.0 mL) was added3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide(Preparation 65, 4.5 mmol, 1280 mg). The reaction mixture was heated at80° C. After stirring for overnight at 80° C., the reaction was cooledto room temperature and poured into 1 N aqueous HCl (100 mL) toprecipitate which was filtered to obtain solid. The solid was washedwith water (100 mL) and heptane (100 mL) and the solid was dried undervacuum to furnish the title compound. LCMS Rt=3.05 minutes MS m/z 451[M(79Br)H]+, 453 [M(81Br)H]+ ¹HNMR (d₆-DMSO): δ 2.17 (s, 3H), 6.70 (d,1H), 7.25-7.31 (m, 1H), 7.44-7.48 (m, 1H), 7.64-7.69 (m, 1H), 8.01 (dd,1H), 8.34 (d, 1H), 8.52 (s, 1H).

Preparation 52N-(5-chloro-thiazol-2-yl)-3-cyano-4-fluorobenzenesulfonamide

To a stirred mixture of 2-amino-5-chlorothiazole-hydrochloride (3.76 g,22.0 mmol) in dichloromethane (20 ml) was added pyridine (8.09 ml, 100mmol). 3-cyano-4-fluorobenzenesulfonyl chloride (4.39 g, 20 mmol)dissolved in dichloromethane (5 mL) and was added to the reactionmixture dropwise at room temperature. After stirring for 48 hours atroom temperature, 1 N HCl (100 mL) was poured into the reaction and themixture was extracted with dichloromethane/methanol (v/v=95/5, 100 ml)three times. The collected organic layer was evaporated in vacuo anddried over MgSO₄ to obtain the crude residue. The crude residue waswashed with dichloromethane (10 mL) and filtered to afford pale yellowsolid as the title compound. LCMS Rt=1.39 minutes MS m/z 318 [M³⁵ClH]+,320 [M³⁷ClH]+ ¹HNMR (d₆-DMSO): δ 7.59 (s, 1H), 7.66-7.73 (m, 1H),8.15-8.21 (m, 1H), 8.33-8.37 (m, 1H).

Preparation 55 4-(biphenyl-2-yloxy)-3-cyanobenzenesulfonyl chloride

A mixture of 5-benzylsulfamyl-2-(biphenyl-2-yloxy)-benzonitrile(Preparation 56, 6.06 g, 15.4 mmol), dichloromethane and aq HCl wasstirred vigorously with cooling (ice bath). Sodium hypochlorite wasadded dropwise over 30 minutes and stirring continued with cooling for 1hour. The layers were separated, the aqueous extracted withdichloromethane (2×100 ml), and the organic collected, dried (MgSO₄) andconcentrated in vacuo. The residue was purified using silica gel columnchromatography (ethyl acetate:Heptane 10/90 to 20/80) to furnish 4.58 gof the title compound. ¹HNMR (CDCl₃): δ 6.7 (m, 1H), 7.2-7.6 (m, 9H),7.85 (m, 1H), 8.15 (m, 1H).

Preparation 56 5-benzylsulfamyl-2-(biphenyl-2-yloxy)-benzonitrile

To a stirred mixture of 2-(biphenyl-2-yloxy)-5-bromo-benzonitrile(Preparation 57, 10.1 g, 28 8 mmol), Pd₂dba₃ (1.32 g, 1.44 mmol), andxantphos (1.67 g, 2.88 mmol) in diisopropylether (10 ml) and 1,4-dioxane(100 ml) was added benzyl mercaptan (3.58 g, 28 8 mmol) and the reactionheated at gentle reflux for 4 to 5 hours, then stirred at ambienttemperature for 30 hours. The reaction mixture was evaporated and theresidue purified using silica gel column chromatography, eluting withdichloromethane/heptane (30/70, then 50/50, then 60/40), to furnish 6.08gm pale yellow solid as the title compound. LCMS Rt=1.88 minutes MS m/z394 [MH]+¹HNMR (CDCl₃): δ 3.93 (s, 2H) 6.46 (d, J=8.58 Hz, 1H) 7.06-7.18(m, 4H) 7.21-7.30 (m, 4H) 7.31-7.43 (m, 5H) 7.45-7.55 (m, 3H)

Preparation 57 2-(biphenyl-2-yloxy)-5-bromo-benzonitrile

A suspension of 5-bromo-2-fluorobenzonitrile (6.48 g, 32.4 mmol),2-phenylphenol (5.79 g, 34 mmol) and potassium carbonate (4.92 g, 35.6mmol) in DMF (50 ml) was heated at 70° C. for 3 hours. The reaction wascooled and quenched by the addition of water (200 ml) followed byextraction with tBuOMe. The organic layer was dried (MgSO₄) andconcentrated in vacuo. The residue was purified using silica gel columnchromatography (ethyl acetate:Heptane 5:95 to 15:85) to furnish 10.1 gof the desired compound. LCMS Rt=1.78 min MS m/z 349 [M]+¹HNMR(d₆-DMSO): δ 6.6 (m, 1H), 7.2-7.6 (m, 9H), 7.65 (m, 1H), 8.0 (m, 1H).

Preparation 58 4-(biphenyl-2-yloxy)-3-cyano-benzenesulfonic acidpentafluorophenyl ester

A solution of 4-(biphenyl-2-yloxy)-3-cyano-benzenesulfonyl chloride(Preparation 55, 500 mg, 1.35 mmol) in dichloromethane (5 ml) was addedslowly to pentafluorophenol (249 mg, 1.35 mmol) and Et₃N (137 mg, 1.35mmol) in dichloromethane (5 ml) and stirring continued overnight atambient temperature. The reaction was concentrated in vacuo and purifiedusing silica gel column chromatography (dichloromethane/heptane 40/60,then 60/40, then 80/20, then dichloromethane) to furnish the titlecompound. LCMS Rt=1.92 minutes ¹H NMR (400 MHz; CDCl₃) δ (ppm): 6.69 (d,J=8.98 Hz, 1H) 7.21-7.30 (m, 2H) 7.31-7.38 (m, 2H) 7.43-7.53 (m, 4H)7.53-7.58 (m, 1H) 7.79 (dd, J=8.98, 2.34 Hz, 1H) 8.06 (d, J=2.34 Hz, 1H)¹⁹F NMR (376 MHz, CDCl₃) δ (ppm): 160.82 (t, J=19.50 Hz)-154.87 (t,J=21.80 Hz)-151.09 (d, J=17.21 Hz)

Preparation 60N-tert-butyl-3,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide andN-[3-tert-butyl-3H-thiazol-(2Z)-ylidene]-3,4-difluorobenzenesulfonamideor(Z)—N-(3-tert-butylthiazol-2(3H)-ylidene)-3,4-difluorobenzenesulfonamide

To a solution of 3,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide(Preparation 61, 50 g, 0.2 mol) in tetrahydrofuran (500 mL) was added4-dimethylaminopyridine (22 g, 0.18 mol) and di-tert-butyldicarbonate(200 g, 0.9 mol) and the mixture was heated to 50° C. for 4 days. Thedi-tert-butyldicarbonate was added portionwise every few hours, usuallyin conjunction with a precipitate that would form and then go back intosolution after the addition. After cooling to room temperature thereaction was concentrated and absorbed onto silica gel and purified byflash column chromatography (ethyl acetate:Hexanes 0-100% ethylacetate). This provided the two products in a 4:1 A:B ratio.

A=N-tert-butyl-3,4-difluoro-N-thiadiazol-2-yl-benzenesulfonamide:

LCMS Rt=1.66 minutes MS m/z 333 [MH]+¹H NMR (CDCl₃) δ 8.02 (m, 1H), 7.89(m, 1H), 7.73 (d, 1H), 7.45 (d, 1H), 7.33 (m, 1H), 1.43 (s, 9H).

B=N-[3-tert-butyl-3H-thiazol-(2Z)-ylidene]-3,4-difluorobenzenesulfonamide:

LCMS Rt=1.51 minutes MS m/z 333 [MH]+¹H NMR (CDCl₃) δ 7.69 (m, 2H), 7.20(m, 1H), 7.07 (d, 1H), 6.42 (d, 1H), 1.57 (s, 9H).

Preparation 61 3,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide

To a slurry of 2-aminothiazole (23.88 g, 0.2384 mol) in methylenechloride (150 mL) and pyridine (38.0 mL, 0.470 mol) was added dropwise asolution of 3,4-difluorobenzenesulphonyl chloride (25.0 g, 0.118 mol) in10 mL of methylene chloride. After stirring for 48 hours the reactionwas diluted with more dichloromethane and extracted with 1N HCl. Theorganic layer was dried over sodium sulfate, filtered, and concentrated.The residue was purified by flash column chromatography to give3,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide as a white solid. LCMSRt=1.24 minutes MS m/z 277 [MH]+

Preparation 62N-tert-butyl-2,4-difluoro-(N-thiazol-2-yl)benzenesulfonamide andN-[3-tert-butyl-3H-thiazol-(2Z)-ylidene]-2,4-difluorobenzenesulfonamide

To a solution of 2,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide(Preparation 63, 11.3 g, 0.0409 mol) in tetrahydrofuran (200 mL) wasadded 4-dimethylaminopyridine (5.0 g, 0.041 mol) anddi-tert-butyldicarbonate (26.8 g, 0.123 mol) and heated to 40° C. for 3days. The di-tert-butyldicarbonate was added portion-wise every fewhours, usually in conjunction with a precipitate that would form andthen go back into solution after the addition. After cooling to roomtemperature the reaction was concentrated and absorbed onto silica geland purified by flash column chromatography. This provided the twoproducts in a 5.5:1 A:B ratio.

A=N-tert-butyl-2,4-difluoro-N-thiadiazol-2-yl-benzenesulfonamide:

LCMS Rt=1.92 minutes MS m/z 333 [MH]+¹H NMR (CDCl₃) δ 8.03 (m, 1H), 7.67(d, 1H), 7.42 (d, 1H), 6.96 (m, 2H), 1.49 (s, 9H).

B=N-[3-tert-butyl-3H-thiazol-(2Z)-ylidene]-2,4-difluorobenzenesulfonamide:

LCMS Rt=1.54 minutes MS m/z 333 [MH]+¹H NMR (CDCl₃) δ 8.07 (m, 1H), 7.12(d, 1H), 6.95 (m, 2H), 6.47 (d, 1H), 1.70 (s, 9H).

Preparation 63 2,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide

To a slurry of 2-aminothiazole (15.08 g, 0.1506 mol) in methylenechloride (100 mL) and pyridine (24 mL, 0.30 mol) was added dropwise over20 minutes a solution of 2,4-difluorobenzenesulfonyl chloride (10 mL,0.07 mol) in 10 mL of methylene chloride. After stirring at roomtemperature for 48 hours the reaction was concentrated and purified byflash column chromatography eluting with hexane/ethyl acetate. LCMSRt=1.21 minutes MS m/z 277 [MH]+

Preparation 653-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Sodium hydroxide (5.08 g, 0.127 mol) was dissolved in water (60 mL) and1,4-1,4-dioxane (300 mL). 1,2,4-Thiadiazol-5-amine (10 g, 0.1 mol) wasadded and the reaction stirred for 5 minutes.3-Cyano-4-fluorobenzene-1-sulfonyl chloride (8.25 g, 0.0376 mol) wasadded and the reaction was allowed to stir for 3 hours at 20° C. Afterthis time, the reaction was poured into 150 mL of 1N HCl. This solutionwas extracted with ethyl acetate (3×50 mL). The combined organics weredried over sodium sulfate, filtered and concentrated to give the titlecompound as a brown solid. LCMS Rt=1.22 minutes MS m/z 283 [MH]+¹H NMR(d₆-DMSO) δ 8.54 (s, 1H), 8.39 (dd, 1H), 8.19 (m, 1H), 7.71 (m, 1H).

Preparation 683-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

(2,4-Dimethoxy-benzyl)-(1,2,4)thiadiazol-5-yl-amine (Preparation 14,8.010 g, 0.03200 mol) was dissolved in tetrahydrofuran (100 mL, 1.3 mol)and cooled to −78° C. 1.0 M of Lithium hexamethyldisilazide intetrahydrofuran (35.2 mL) was added dropwise to the reaction mixture.The cooling bath was removed and the reaction was allowed to stir for 30minutes. The reaction was cooled back to −78° C. and a solution of3-cyano-4-fluorobenzenesulfonyl chloride (7.028 g, 0.03200 mol) intetrahydrofuran (80 mL, 0.99 mol) was added dropwise to the reaction.The reaction was allowed to stir for 30 minutes at −78° C. The reactionwas poured into saturated aqueous ammonium chloride. The aqueous phasewas extracted with ethyl acetate (three times). The combined organicphase was washed twice with 10% citric acid solution, water and brine.The organic phase was dried over magnesium sulfate and evaporated to aresidue. The residue was purified by column chromatography (120 g silicagel column, Hexanes to ethyl acetate gradient elution). Productfractions were combined and evaporated to a residue. The residue wastriturated with 10% t-butyl methyl ether in hexanes and the resultingoff-white solid collected by filtration and rinsed with hexanes. Vacuumdrying gave 3.58 g of the title compound. LCMS Rt=1.66 minutes MS m/z457 [M Na]+. MS m/z 151 [MH]+ 2,4-Dimethoxybenzyl ¹H NMR (d₆-DMSO) δ8.44 (s, 1H) 8.33 (dd, 1H), 8.25 (m, 1H), 7.72 (t, 1H), 7.03 (d, 1H),6.43 (m, 2H), 5.23 (s, 2H), 3.73 (s, 3H), 3.64 (s, 3H).

Preparation 72

thiazole-4-yl-carbamic acid tert-butyl ester

Thiazole-4-carboxylic acid (6.46 g, 50.0 mmol) was slurried intert-butyl alcohol (280 mL, 2900 mmol). Triethylamine (7.68 mL, 55.1mmol) and diphenylphosphonic azide (11.9 mL, 55.1 mmol) were added andthe reaction was heated at reflux for 18 hours. The reaction wasevaporated to a residue. The residue was dissolved in ethyl acetate andwashed with water, 5% citric acid (aqueous), water, saturated aqueoussodium bicarbonate and brine. The organic phase was dried over magnesiumsulfate and evaporated to a residue. The residue was purified by silicagel chromatography (80 g ISCO™ column, hexanes to ethyl acetate gradientelution). Product fractions were combined and evaporated to a residue.The residue was triturated with 20% methyl t-butyl ether in hexanes. Thesolid was collected by filtration. Vacuum drying gave 6.48 g of productas a white solid. LCMS Rt=1.46 minutes MS m/z 201 [MH]+

Preparation 88 4-fluoro-2-(1-methyl-1H-pyrazol-5-yl)phenol and4-fluoro-2-(1-methyl-1H-pyrazol-3-yl)phenol

To a suspension of 6-fluorochromone (2.01 g, 0.0122 mol) in ethanol (40mL) was added methylhydrazine sulfate (1.91 g, 0.0132 mol) andtriethylamine (2.2 mL, 0.016 mol). The reaction was heated to reflux for18 hours. After cooling, the reaction was concentrated in vacuo and theresidue purified by flash column chromatography eluting withhexane/ethyl acetate. Two regioisomeric products in a 1:2 A:B ratio wereobtained with the major being the less polar and the minor being morepolar.

A=4-fluoro-2-(1-methyl-1H-pyrazol-5-yl)phenol

LCMS Rt=1.28 minutes MS m/z 193 [MH]+

1H NMR (CDCl₃) δ 7.54 (d, 1H), 7.07-6.91 (m, 4H), 6.33 (d, 1H), 3.78 (s,3H).

B=4-fluoro-2-(1-methyl-1H-pyrazol-3-yl)phenol

LCMS Rt=1.43 minutes MS m/z 193 [MH]+

1H NMR (CDCl₃) δ 10.64 (s, 1H), 7.44 (d, 1H), 7.27 (dd, 1H), 6.97 (m,2H), 6.59 (d, 1H), 3.99 (s, 3H).

Preparation 89 4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenol and4-chloro-2-(1-methyl-1H-pyrazol-3-yl)phenol

To a suspension of 6-chlorochromone (2.00 g, 0.0111 mol) in ethanol (35mL) was added methylhydrazine sulfate (1.85 g, 0.0128 mol) andtriethylamine (2.0 mL, 0.014 mol). The reaction was heated to reflux for18 hours. After cooling, the reaction was concentrated in vacuo and theresidue purified by flash column chromatography eluting with 0-100%hexane/ethyl acetate gradient. Two regioisomeric products in a 1:4 A:Bratio were obtained with the major being the less polar and the minorbeing more polar.

A=4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenol

LCMS Rt=1.43 minutes MS m/z 209 [MH]+

1H NMR (CDCl₃) δ 7.65 (d, 1H), 7.34 (dd, 1H), 7.22 (d, 1H), 6.99 (d,1H), 6.40 (d, 1H), 5.52 (m, 1H), 2.96 (s, 3H).

B=4-chloro-2-(1-methyl-1H-pyrazol-3-yl)phenol

LCMS Rt=1.58 minutes MS m/z 209 [MH]+

1H NMR (CDCl₃) δ 10.85 (s, 1H), 7.54 (d, 1H), 7.44 (d, 1H), 7.17 (dd,1H), 7.00 (d, 1H), 6.61 (d, 1H), 3.98 (s, 3H).

Preparation 92 2-(1-methyl-1H-pyrazol-5-yl)phenol and2-(1-methyl-1H-pyrazol-3-yl)phenol

Prepared by the process described by J. Catalan et. al in JACS, 1992,114, 5039. Two regioisomeric products in a 1:1 A:B ratio were obtained.

A=2-(1-methyl-1H-pyrazol-5-yl)phenol

LCMS Rt=1.31 minutes MS m/z 175 [MH]+

¹H NMR (CDCl₃) δ 7.62 (d, 1H), 7.39 (m, 1H), 7.26 (dd, 1H), 7.06 (m,2H), 6.39 (d, 1H), 6.34 (m, 1H), 3.83 (s, 3H).

B=2-(1-methyl-1H-pyrazol-3-yl)phenol

LCMS Rt=1.45 minutes MS m/z 175 [MH]+

¹H NMR (CDCl₃) δ 10.94 (s, 1H), 7.62 (dd, 1H), 7.42 (d, 1H), 7.25 (m,1H), 7.08 (dd, 1H), 6.95 (m, 1H), 6.64 (d, 1H), 3.98 (s, 3H).

Preparation 1904-(2-tert-butyl-5-trifluoromethyl-2H-pyrazol-3-yl)-phenol

A mixture of 4,4,4-trifluoro-1-(4-hydroxyphenyl)butane-1,3-dione (500mg, 0.002 mol) and tert-butylhydrazine hydrochloride (270 mg, 0.0022mol) in ethanol (12 mL, 0.21 mol) was heated at 150° C. in microwave for1 h. Solvent was removed and the residue was purified via automatedflash chromatography (silica gel, 0% to 30% ethyl acetate in hexanes) togive the product as an off-white solid (0.36 g, 60%). LCMS Rt=1.75minutes

MS m/z 285 [MH]+

Preparation 205 tert-Butyl4-(5-chloro-2-hydroxyphenyl)-1H-pyrazole-1-carboxylate

A suspension of 4-chloro-2-iodophenol (200 mg, 0.78 mmol) and potassiumcarbonate (434 mg, 3.14 mmol) in 1,4-dioxane (3 mL) and water (1 mL) wasdegassed and heated for 1 hour at 50° C. tert-Butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(347 mg, 1.18 mmol) and palladium (0) tetrakis(triphenylphoshine) (91mg, 0.08 mmol) were added and the mixture heated at 50° C. for 5 hours.Dichloromethane (20 ml) and water (10 ml) were added and the organicsseparated and evaporated in vacuo. The residue was purified by columnchromatography (silica gel) eluting with ethyl acetate:heptane (2:8 to1:0, by volume) to afford the title product as a white solid, 155 mg,66% yield.

LCMS Rt 3.03 minutes. MS m/z 195 [M³⁵Cl(-BOC)H]+

¹HNMR (d₆-DMSO): δ 1.60 (s, 9H), 6.90 (m, 1H), 7.15 (m, 1H), 7.80 (m,1H), 8.40 (m, 1H), 8.65 (m, 1H), 10.40 (s, 1H).

Preparation 207N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-N-(2,4-dimethoxybenzyl)-4-fluorobenzenesulfonamide

Under an atmosphere of nitrogen,5-chloro-N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 208,3.0 g 10.5 mmol) was dissolved in tetrahydrofuran (20 ml) and cooled to−70° C. Lithium hexamethyldisilazane (1 M in tetrahydrofuran, 12.6 ml,12.6 mmol) was added dropwise, keeping the temperature below −60° C.After 5 minutes, the cooling bath was removed and the reaction warmed toroom temperature, stirred for a further 5 minutes then cooled back to−70° C. 3-Cyano-4-fluorobenzenesulfonyl chloride (2.54 g, 11.6 mmol) intetrahydrofuran (10 ml) was added dropwise keeping the temperature below−60° C. and the reaction mixture was warmed to room temperature.Saturated aqueous ammonium chloride solution (50 ml) was added followedby water to dissolve the solid which had precipitated out. The aqueouslayer was extracted with ethyl acetate (50 ml) and the organic extractsdried over magnesium sulphate and decolourising charcoal, filteredthrough Celite™ and the filtrate evaporated in vacuo. The resulting gumwas purified using a short column (silica gel, 150 g) eluting with ethylacetate:heptane (1:1, by volume) affording a gum which was trituratedwith tert-butyl ether, filtered, washed with heptane and dried in vacuoto give the title compound as a buff solid, 2.84 g, 57% yield.

LCMS Rt=4.65 minutes. MS m/z 468

¹HNMR (CDCl₃): δ 3.68 (s, 3H), 3.80 (s, 3H), 4.99 (s, 2H), 6.34 (d, 1H),6.39 (dd, 1H), 7.12 (d, 1H), 7.28 (s, 1H), 7.31 (t, 1H), 7.98 (dd, 1H),8.05 (m, 1H). ¹⁹FNMR (CDCl₃): δ −98.51 (m, 1 F)

Preparation 208 5-Chloro-N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine

Nitrogen was bubbled through a suspension of 2-amino-5-chlorothiazolehydrochloride (25.0 g, 146 mmol) in dichloromethane (1000 ml) for 10minutes before the addition of piperidine (13.0 g, 15.0 ml, 150 mmol)via syringe. 2,4-Dimethoxybenzaldehyde (22.1 g, 133 mmol) was addedfollowed by freshly dried 3 Å molecular sieves (ca. 40 g). The mixturewas stirred at 45° C. under nitrogen fro 16 hours. Upon cooling to roomtemperature the mixture was filtered through a pad of Celite™, washingwith dichloromethane (2000 ml) before concentrating in vacuo to give ayellow solid, 58.2 g. This residue was dissolved in methanol (1250 ml)and sodium borohydride (13.0 g, 340 mmol) was added portionwise. Uponcomplete addition the mixture was heated to 50° C. for 30 minutes beforecooling to room temperature and stirring under nitrogen for 16 hours.The solvent was concentrated in vacuo and the residue partitionedbetween ethyl acetate (300 ml) and water (500 ml). The layers wereseparated and the aqueous was extracted with ethyl acetate (3×300 ml).The combined organics were washed with water (300 ml), saturated aqueoussodium chloride solution (300 ml), dried over magnesium sulphate,filtered and concentrated in vacuo to give a red-brown solid, 41.6 g.This residue was dissolved in ethyl acetate and passed through a plug ofsilica. Concentration in vacuo afforded a red-brown solid, 39.3 g, whichwas subsequently triturated with diethyl ether (ca. 500 ml) and stirredfor 60 hours. The solid was filtered and air-dried to give the titlecompound as a white solid, 12.1 g, 32% yield. The mother liquor wasconcentrated in vacuo to give a brown solid, 25 g, which was stirred indiethyl ether:heptane (2:3, 500 ml). The solid material was filtered andair-dried to give the title compound as an off-white solid, 13.2 g, 35%yield.

¹HNMR (d₆-DMSO): δ 3.65 (s, 3H), 3.75 (s, 3H), 4.2 (m, 2H), 6.4 (m, 1H),6.5 (s, 1H), 6.9 (s, 1H), 7.1 (m, 1H), 7.9 (m, 1H).

Preparation 209N-[1-tert-butyl-4-(5-chloro-2-hydroxyphenyl)-1H-pyrazol-5-yl]-2,2,2-trifluoroacetamide

To a solution of (5-chloro-2-methoxy-phenyl)acetonitrile (Preparation210, 2.154 g, 11.86 mmol) in ethyl formate (20 ml) was added sodium (605mg, 26.3 mmol). The reaction was heated at a gentle reflux for 16 hours.After cooling to room temperature, water and dichloromethane were addedand the solution adjusted to pH 3 with hydrochloric acid (6 M aqueoussolution). The layers were separated and the aqueous layer extractedwith dichloromethane (2×50 ml). The combined organics were washed withsaturated aqueous sodium chloride solution, dried over magnesiumsulphate, filtered and evaporated in vacuo. Purification by flash columnchromatography eluting with ethyl acetate:hexanes (gradient 0:1 to 1:1,by volume) gave a white solid which was dissolved in ethanol (50 ml),tert-butylhydrazine hydrochloride (1.77 g, 14.2 mmol) added and solutionheated to reflux for 24 hours. The reaction was cooled and evaporated invacuo to give a brown oil. This oil was dissolved in dichloromethane (50ml) and triethylamine (4.2 ml, 30 mmol) and trifluoroacetic anhydride(4.2 ml, 30 mmol) were added. After stirring for 16 hours, the reactionwas washed with potassium hydrogen sulphate (1 N aqueous solution),sodium bicarbonate (1 N aqueous solution) and saturated aqueous sodiumchloride solution. The organic layer was separated, dried over magnesiumsulphate, filtered and concentrated in vacuo to give a brown oil. Thisoil was dissolved in dichloromethane (20 ml) and cooled over an icewater bath before the addition of boron tribromide (1 M indichloromethane, 22 ml, 22 mmol). After stirring for 45 minutes thereaction was added to ice water. The layers were separated and theaqueous layer washed with dichloromethane (2×20 ml). The combinedorganics were dried over magnesium sulfate, filtered and concentrated invacuo to give a brown oil. Purification by flash column chromatographyeluting with ethyl acetate:hexane (gradient 0:1 to 1:0, by volume) toafford the title compound as a brown oil that solidified to a tan solidupon standing, 2.82 g, 66% yield.

LCMS Rt 1.61 minutes. MS m/z 362 [MH]+

¹HNMR (CDCl₃): δ 1.69 (s, 9H), 6.87 (m, 1H), 7.16 (m, 2H), 7.64 (s, 1H),8.74 (s, 1H).

Preparation 210 (5-Chloro-2-methoxy-phenyl)acetonitrile

To a solution of methyl 5-chloro-2-methoxybenzoate (25.4 g, 127 mmol) inether (200 ml), cooled in an ice water bath, was added dropwise lithiumtetrahydroaluminate (1 M in diethyl ether, 110 ml, 110 mmol). After 2hours the reaction was quenched with water and then acidified to pH 3with hydrochloric acid (6 M aqueous solution). The layers were separatedand the organic layer dried over magnesium sulfate, filtered andconcentrated in vacuo to give a white solid. The solid was dissolveddichloromethane (200 ml) and treated with thionyl chloride (25 ml, 340mmol). After heating at reflux for 2 hours, the reaction was cooled toroom temperature and water added. The layers were separated and theaqueous layer extracted with dichloromethane (2×50 ml). The combinedorganics were dried over magnesium sulfate, filtered and concentrated invacuo to give an orange solid. This solid was dissolved dimethylsulphoxide (175 ml), sodium cyanide (12.75 g, 260.2 mmol) added andsolution heated to 80° C. for 3 hours. After cooling to roomtemperature, water was added and a solid formed that was filtered andwashed with water to provide the title compound as an off white solid,20.8 g, 91% yield.

LCMS Rt 1.55 minutes.

¹HNMR (CDCl₃): δ 3.70 (s, 2H), 3.90 (s, 3H), 6.84 (d, 1H), 7.30 (m, 1H),7.39 (m, 1H).

Preparation 211 tert-Butyl[4-(5-fluoro-2-hydroxyphenyl)pyridin-2-yl]carbamate

4-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol(Preparation 212, 0.082 g, 0.000386 mol), tert-butyl(4-chloropyridin-2-yl)carbamate (0.0588 g, 0.000257 mol), anhydroussodium carbonate (0.070 g, 0.000660 mol) and palladium (0)tetrakis(triphenylphosphine) (0.029 mg, 0.000025 mol) were suspended in1,4-dioxane (3.0 ml) and water (1.0 ml). The suspension was stirred at85° C. for 16 hours before cooling to room temperature. The reaction wasdiluted with ethyl acetate (10 ml) and organic phase was washed withsaturated aqueous sodium bicarbonate solution (2×10.0 ml), dried oversodium sulphate, filtered and concentrated in vacuo. Purification byISCO™ (12 g SiO₂) eluting with ethyl acetate:heptane (gradient 0:1 to3:7, by volume) afforded the title compound as a solid, 41 mg, 54%.

LCMS Rt=1.40 minutes MS m/z 303 [MH]+

¹H NMR (400 MHz, d₆-DMSO): δ 1.45 (s, 9H), 6.95 (m, 1H), 7.05 (m, 1H),7.15 (m, 1H), 7.20 (d, 1H), 8.00 (s, 1H), 8.25 (d, 1H), 9.65 (s, 1H),9.75 (s, 1H)

Preparation 2124-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

To a suspension of (5-fluoro-2-hydroxyphenyl)boronic acid (1.000 g,0.00641 mol) in toluene (3.0 ml) was added pinacol (0.875 g, 0.007404mol). This was heated to reflux using a Dean-Stark apparatus for 24hours before concentrating in vacuo. The residue was suspended intert-butyl-methyl ether (10.0 ml) and organic layer was washed withsaturated aqueous sodium chloride solution (2×10.0 ml), dried oversodium sulphate, filtered and concentrated in vacuo to afford the titlecompound as a translucent oil, 1.4 g, 92% yield.

¹HNMR (CDCl₃): δ 1.35 (s, 12H), 6.80 (dd, 1H), 7.05 (dt, 1H), 7.35 (dd,1H), 7.60 (s, 1H).

Preparation 217N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-N-(2,4-dimethoxybenzyl)-4-(4-fluoro-2-iodophenoxy)benzenesulfonamide

N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-N-(2,4-dimethoxybenzyl)-4-fluorobenzenesulfonamide(Preparation 207, 410 mg, 0.876 mmol), 2-iodo-4-fluorophenol(Preparation 218, 229 mg, 0.964 mmol) and potassium carbonate (363 mg,2.63 mmol) in dimethyl sulphoxide (20 ml) were stirred at roomtemperature under nitrogen for 18 hours. The reaction mixture was pouredinto water (50 ml) and extracted with ethyl acetate (3×30 ml). Thecombined organics were washed with saturated aqueous sodium chloridesolution (30 ml), dried over magnesium sulfate, filtered andconcentrated in vacuo to give the title compound as an off-white solid,670 mg, quantitative yield.

LCMS R_(t) 3.50 minutes.

¹HNMR (d₆-DMSO): δ 3.6 (s, 3H), 3.7 (s, 3H), 4.9 (s, 2H), 6.4 (m, 2H),6.8 (m, 1H), 7.0 (m, 1H), −7.4 (m, 2H), 7.55 (s, 1H), 7.9 (m, 1H), 8.0(m, 1H), 8.35 (m, 1H).

Preparation 218 4-Fluoro-2-iodophenol

N-Iodosuccinimide (10 g, 45.0 mmol) and 4-fluoro-phenol (5.00 g, 40.0mmol) were suspended in acetic acid (39 ml, 649.0 mmol) and stirred for5 minutes before addition of concentrated sulphuric acid (0.79 ml, 13.4mmol). The reaction mixture was stirred for 18 hours at room temperaturebefore diluting with water (100 ml). The aqueous layer was extractedwith dichloromethane (2×30 ml). The combined organic extracts werewashed with sodium thiosulphate solution (20% aqueous, wt:v), water,dried over sodium sulfate, filtered and concentrated in vacuo. The cruderesidue was purified by column chromatography (silica gel) eluting withtoluene to afford the title compound as an off white solid, 4.5 g, 40%yield.

LCMS Rt=1.33 minutes. MS m/z 237 [MH]⁻

¹H NMR (400 MHz, CDCl₃) δ: 5.22 (s, 1H), 6.99 (m, 2H), 7.42 (dd, 1H)ppm.

Preparation 2194-(4-Chloro-2-iodophenoxy)-N-(5-chloro-1,3-thiazol-2-yl)-3-cyanobenzenesulfonamide

To a stirred suspension of 4-chloro-2-iodophenol (305 mg, 1.20 mmol) andpotassium carbonate (207 mg, 1.5 mmol) in dimethyl sulphoxide (5.0 ml)was addedN-(5-chloro-1,3-thiazol-2-yl)-3-cyano-N-(2,4-dimethoxybenzyl)-4-fluorobenzenesulfonamide(Preparation 207, 468 mg, 1.00 mmol). Suspension stirred at roomtemperature for 18 hours. The reaction mixture was poured into ethylacetate (20 ml) and saturated aqueous ammonium chloride solution (20 ml)and the aqueous layer extracted with ethyl acetate (3×20 ml). Combinedorganic layers were dried over magnesium sulfate and concentrated invacuo. The crude residue was dissolved in dichloromethane (5 ml),trifluoroacetic acid (5 ml) was added and the reaction mixture wasstirred at room temperature for 2 hours. The solvent was concentrated invacuo and purified by ISCO™ preparative system eluting withdichloromethane:ethyl acetate (gradient 1:0 to 6:4, by volume) to affordthe title compound as a solid, 396 mg, 72% yield.

LCMS Rt 3.43 minutes. MS m/z 552 [M³⁵ClH]⁺

¹HNMR (d₆-DMSO): δ 6.86 (d, 1H), 7.43 (d, 1H), 7.55 (s, 1H), 7.62 (dd,1H), 7.99 (dd, 1H), 8.09 (d, 1H), 8.29 (d, 1H).

Preparation 221(2E)-3-(Dimethylamino)-1-(5-fluoro-2-hydroxyphenyl)prop-2-en-1-one

To a solution of 4-fluoro-2-hydroxyacetophenone (13.0 g, 84.4 mmol) inisopropanol (150 ml), was added dimethylformamide dimethylacetal (20.1g, 169 mmol). The resulting yellow solution was heated at 45° C. withoutstirring for 18 hours before cooling to room temperature. The resultingcrystalline yellow solid was isolated by filtration and washed with aminimum of cold isopropanol. The filtrate concentrated in vacuo to 30 mland the resulting yellow solution cooled to 5° C., resulting inprecipitation of a further batch of yellow solid. The solid was isolatedby filtration, washing with a minimum of cold isopropanol and combinedwith the original batch to afford the title compound, 17.0 g, 96% yield.

LCMS Rt 2.02 minutes.

¹HNMR (CDCl₃): δ 2.97 (s, 3H), 3.20 (s, 3H), 5.64 (m, 1H), 6.86 (m, 1H),7.07 (m, 1H), 7.36 (m, 1H), 7.91 (m, 1H).

Preparation 224 2-Iodo-4-(trifluoromethyl)phenol

To a suspension of N-iodosuccinimide (11.10 g, 49.5 mmol) in glacialacetic acid (40 ml) was added 4-trifluoromethyl phenol (8.02 g, 49.5mmol) and, after 5 minutes, concentrated sulphuric acid (0.87 ml, 14.8mmol). The pale brown/red suspension was stirred at room temperatureunder nitrogen for 48 hours before diluting with water and extractingwith dichloromethane. The organic extract was washed with water,saturated aqueous sodium thiosulphate solution, water, dried overmagnesium sulphate before decolourising charcoal added. The suspensionwas left to stand for 10 minutes before filtering through a short pad ofsilica gel eluting with dichloromethane. The solvent was evaporated invacuo to give an oil which was purified by flash column chromatographyon silica eluting with dichloromethane to give the title compound as apale yellow oil, 9.017 g, 63% yield.

LCMS Rt=1.53 minutes. MS m/z 287 [MH]⁻

¹H NMR (400 MHz, CDCl₃): δ 5.79 (br s, 1H), 7.05 (d, 1H), 7.51 (dd, 1H),7.93 (d, 1H) ppm.

Method 2

Preparation 224 can also be prepared as follows.

N-iodosuccinimide (69.5 g, 0.309 moles) was suspended in acetic acid(257 mL) and cooled to 0° C. 4-Trifluoromethylphenol (50.0 g, 0.310moles) was added followed by sulphuric acid (5.44 mL) dropwise over 5minutes. The orange-brown suspension was stirred whist warming slowly toroom temperature over 18 hours. A further portion of N-iodosuccinimide(2.5 g, 0.011 moles) was added and the mixture was stirred at roomtemperature for 24 hours. The reaction was quenched by adding water (150mL) and extracted with dichloromethane (2×100 mL). The combined organicswere washed with a saturated aqueous solution of sodium metabisulphite(2×50 mL) and then with saturated aqueous sodium chloride solution (50mL). The organics were dried over anhydrous magnesium sulphate, filteredand the solvents removed in vacuo to give the crude title product as alight yellow oil. This batch was combined with the products from twofurther identical reactions and purified by distillation in vacuo. Theproduct was collected boiling at approximately 45° C. at 2 mBar to givethe title compound as a pink-orange semi-solid (216 g).

LCMS Rt=2.89 minutes. MS m/z=287 [M−H]−

¹HNMR (CDCl₃): δ 5.62 (br s, 1H), 7.03 (d, 1H), 7.51 (d, 1H), 7.92 (s,1H).

Preparation 226 2-Iodo-4-(trifluoromethoxy)phenol

To a suspension of N-iodosuccinimide (6.95 g, 31 mmol) in glacial aceticacid (2 ml) was added 4-trifluoromethoxy phenol (4.0 ml, 31 mmol) and,after 5 minutes, concentrated sulphuric acid (0.5 ml, 9 mmol). The palebrown suspension was stirred at room temperature under nitrogen for 48hours before diluting with water and extracting with dichloromethane.Organic extract was washed with water, saturated aqueous sodiumthiosulphate solution, water, dried over magnesium sulfate anddecolourising charcoal added. The resulting suspension was left to standfor 30 minutes before filtering through a short pad of silica geleluting with dichloromethane. The solvent was evaporated in vacuo togive the title compound as an oil, 8.78 g, 94% yield.

LCMS Rt=1.51 minutes. MS m/z 303 [MH]−

¹H NMR (400 MHz, CDCl₃): δ 5.49 (br s, 1H), 6.99 (d, 1H), 7.15 (dd, 1H),7.55 (d, 1H) ppm.

Preparation 231 tert-Butyl4-(5-chloro-2-hydroxyphenyl)piperidine-1-carboxylate

To a suspension of 4-chloro-2-piperidin-4-ylphenol hydrobromide(Preparation 232, 100 mg, 0.342 mmol) andN-ethyl-N-isopropylpropan-2-amine (65.5 μl, 0.376 mmol) indichloromethane (5 ml) at 0° C. was added dropwise a solution ofdi-tert-butyl dicarbonate (82.9 mg, 0.376 mmol) in dichloromethane (1ml). The resulting mixture was warmed to room temperature and stirredfor 16 hours. Water (1 ml) was added and stirred for 5 minutes beforefiltering through a phase separating cartridge. The organics wereevaporated in vacuo to afford the title compound as a pale cream solid,110 mg, 100% yield.

LCMS Rt 1.64 minutes. MS m/z 310 [MH]−

¹HNMR (CDCl₃): δ 1.51 (m, 9H), 1.61 (m, 2H), 1.82 (d, 2H), 2.83 (t, 2H),3.0 (m, 1H), 4.25 (d, 2H), 6.69 (d, 1H), 7.04 (dd, 1H), 7.10 (d, 1H).

Preparation 232 4-Chloro-2-piperidin-4-ylphenol hydrobromide

To 4-(5-chloro-2-methoxyphenyl)piperidine (Preparation 233, 40 g, 0.177mol) was added hydrogen bromide (48% in water, 100 ml) and refluxed for24 hours before concentrating in vacuo. 1,4-Dioxane was added andsolution concentrated in vacuo. The resulting crystals were washed withdiethyl ether and dried in vacuo to give the title compound as whitecrystals, 53 g, 97% yield.

LCMS (7.5 minute acid run) ESI m/z 212 [M³⁵ClH]⁺ Rt 2.25 minutes.

¹HNMR (d₆-DMSO): δ 1.80 (m, 4H), 3.10 (m, 3H), 3.35 (m, 2H), 6.84 (d,1H), 7.02 (m, 1H), 7.11 (m, 1H), 8.30 (brs, 1H), 8.62 (brs, 1H), 9.80(s, 1H).

Preparation 233 4-(5-Chloro-2-methoxyphenyl)piperidine

A solution of benzyl4-(5-chloro-2-methoxyphenyl)piperidine-1-carboxylate (Preparation 234,73 g, 0.2 mol) in concentrated hydrochloric acid (200 ml) was refluxedwith stirring for 2 hours before concentrating in vacuo. Water (100 ml),sodium hydroxide (10 M aqueous solution, 20 ml) and chloroform (200 ml)were added to the residue. The aqueous layer was extracted withchloroform (2×200 ml). The combined organic layers were washed withwater (200 ml), saturated aqueous sodium chloride solution (200 ml),dried over sodium sulphate, filtered through silica gel (100 g, 40/63μm) and evaporated in vacuo to afford the title compound as whitecrystals, 40 g, 89% yield.

Preparation 234

Benzyl 4-(5-chloro-2-methoxyphenyl)piperidine-1-carboxylate

To a solution of tert-butyl4-(5-chloro-2-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate(Preparation 235, 90 g, 0.263 mol) in 1,4-dioxane (200 ml) was addedhydrogen chloride (4 M in dioxane, 150 ml, 0.6 mol) under argon. Themixture was stirred for 24 hours and evaporated in vacuo. Diethyl etherwas added before concentrating in vacuo. Water (300 ml) and diethylether (500 ml) were added to this residue before the addition of sodiumcarbonate (32 g, 0.3 mol) under vigorous stirring. Mixture cooled overan ice bath before the dropwise addition of benzyl chlorocarbonate (43ml, 0.3 mol). The bath was removed and the mixture stirred for 1 hour.The aqueous layer was extracted with ether (2×200 ml). The combinedorganic layers were washed with water (200 ml), saturated aqueous sodiumchloride solution (200 ml), dried over sodium sulfate, filtered throughsilica gel (100 g, 40/63 μm) and evaporated in vacuo. 1,4-Dioxane wasadded and concentrated in vacuo before diluting with dichloromethane(300 ml). Triethylsilane (132 ml, 0.828 mol) and trifluoroacetic acid(96 ml, 1.24 mol) were added under argon and the mixture was stirred for20 hours before concentrating in vacuo. To this residue were addedsaturated aqueous potassium carbonate solution to basify the solution topH 10. Water (200 ml) was added and the aqueous layer was extracted withdiethyl ether. The combined organic fractions were washed with water(2×200 ml), saturated aqueous sodium chloride solution (200 ml), driedover sodium sulphate, filtered through silica gel (100 g, 40/63 μm) andevaporated in vacuo. 1,4-dioxane was added to this residue beforeconcentrating in vacuo. To a solution of this residue in tetrahydrofuran(300 ml), cooled over an ice bath in an atmosphere of argon, was addedborane (1 M in tetrahydrofuran, 260 ml). The mixture was stirred at roomtemperature for 2 hours before cooling over an ice bath in argon andadding acetic acid (260 ml). The mixture was stirred for 24 hours beforeevaporating in vacuo. To this residue were added saturated aqueouspotassium carbonate solution to basify the solution to pH 10. Water (200ml) was added and the aqueous layer was extracted with diethyl ether.The organic fractions were washed with water (2×200 ml), saturatedaqueous sodium chloride solution (200 ml), dried over sodium sulfate andevaporated in vacuo. The residue was purified on silica gel (500 g,60/100 μm) eluting with carbon tetrachloride:ethyl acetate (gradient 1:0to 10:1, by volume) to give the title compound as a yellow oil, 73 g,77% yield.

Preparation 235 tert-Butyl4-(5-chloro-2-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate

To a stirred solution of 2-bromo-4-chloroanisole (164 g, 0.74 mol) intetrahydrofuran (1 L), cooled at −70° C. and under an atmosphere ofargon, was added butyl lithium (2.7 M in heptane, 280 ml) over a periodof 1 hour. The mixture was stirred for 30 minutes, maintaining thetemperature at −70° C., before the addition of N-boc-4-piperidone (145g, 0.73 mol) in tetrahydrofuran (250 ml) over a period of 1 hour. Thereaction temperature was warmed to −40° C. over 2 hours before theaddition of sodium hydrogen sulphate (5M aqueous, 160 ml), sodiumsulphate (300 g) and hexane (500 ml). The mixture was stirred for 10hours. The organic layer was decanted, filtered through silica gel (300g, 63/100 μm) washing with ethyl acetate:hexane (4:6, by volume, 2×400ml). The filtrate was evaporated in vacuo and the residue recrystallizedfrom ethyl acetate:hexane to afford the title compound as whitecrystals, 100 g, 39% yield.

Preparation 237 tert-Butyl3-(5-chloro-2-hydroxyphenyl)azetidine-1-carboxylate

To a solution of tert-Butyl3-(2-{[tert-butyl(dimethyl)silyl]oxy}-5-chlorophenyl)azetidine-1-carboxylate(Preparation 238, 3.1 g, 7.79 mmol) in tetrahydrofuran (80 ml) was addedtetramethylammonium fluoride (1.0 g, 10.74 mmol). The mixture wasstirred at room temperature for 18 hours before concentrating in vacuo.The residue was partitioned between tert-butyl methyl ether (100 ml) andaqueous sodium hydroxide solution. The organics were dried over sodiumsulfate, filtered and evaporated in vacuo to give a reddish brown oil,2.33 g. This was purified by column chromatography (100 g of silica)eluting with heptane:ethyl acetate (6:4, by volume) to afford the titlecompound as a reddish brown gum, 850 mg, 38% yield.

LCMS Rt 1.52 minutes. MS m/z 282 [M³⁵ClH]⁺.

¹HNMR (CDCl₃): δ 1.44 (s, 9H), 3.93 (m, 1H), 4.04 (m, 2H), 4.28 (m, 2H),6.72 (d, 1H), 7.05 (m, 2H).

Preparation 238 tert-Butyl3-(2-{[tert-butyl(dimethyl)silyl]oxy}-5-chlorophenyl)azetidine-1-carboxylate

Zinc powder (700 mg, 10.7 mmol) was suspended in N,N-dimethylformamide(20 ml) under nitrogen. 1,2-dibromoethane (120 ul) was added andsuspension heated to 60° C. for 10 minutes before cooling to roomtemperature. Chlorotrimethylsilane (180 ul) was added and the mixtureheated to 60° C. for 10 minutes then cooled to room temperature.tert-Butyl 3-iodoazetidine-1-carboxylate (3.0 g, 10.6 mmol) was addedwith a slight exotherm observed. The mixture was stirred at roomtemperature for 1 hour before the addition oftert-butyl(4-chloro-2-iodophenoxy)dimethylsilane (Preparation 239, 2.2g, 5.97 mmol) followed immediately by tri-2-furylphosphine (250 mg, 1.08mmol) and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one-palladium (2:1) (300mg, 0.52 mmol). The mixture was stirred at room temperature for 30minutes then heated at 70° C. for 5 hours before concentration in vacuo.The residue was partitioned between ethyl acetate (100 ml) and aqueoussodium carbonate solution (50 ml). The organic extract was dried oversodium sulphate, filtered and evaporated in vacuo to afford the titlecompound as a brown oil, 3.2 g,

LCMS Rt 1.68 minutes. MS m/z 795 [M³⁵ClH]+

Preparation 239 tert-Butyl(4-chloro-2-iodophenoxy)dimethylsilane

To a solution of 4-chloro-2-iodophenol (1.587 g, 6.238 mmol) indichloromethane (10 ml) was added 1H-imidazole (1.01 g, 14.3 mmol)followed by a solution of tert-butyl(chloro)dimethylsilane (2.63 ml,13.7 mmol) in dichloromethane (10 ml) dropwise. The resulting whitesuspension was stirred for 16 hours at room temperature beforeconcentrating in vacuo. The residue was diluted with ethyl acetate (20ml) and water (20 ml). The aqueous phase was acidified with hydrochloricacid (2 M aqueous solution) and extracted with ethyl acetate. Thecombined organic layers were washed with hydrochloric acid (2 M aqueoussolution), saturated aqueous sodium chloride solution, dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography (40 g silica gel column) eluting with ethylacetate:heptane (gradient 0:1 to 3:7, by volume) to afford the titlecompound as pale yellow oil, 2.2 g, 95% yield.

¹HNMR (CDCl₃): δ 0.28 (s, 6H), 1.07 (s, 9H), 6.74 (d, 1H), 7.18 (dd,1H), 7.74 (dd).

Preparation 240N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-(4-fluoro-2-iodophenoxy)benzenesulfonamide

To a solution ofN-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-fluorobenzenesulfonamide(Preparation 52, 100 mg, 0.32 mmol) and potassium carbonate (109 mg, 0.8mmol) in dimethylformamide (3 ml) was added 4-fluoro-2-iodophenol(Preparation 218, 0.32 mmol) and the reaction heated at 80° C. for 24hours. The solution was added dropwise into rapidly stirringhydrochloric acid (2M aqueous solution). The fine dark precipitate wasfiltered and dried in vacuo to afford the title product as a brownsolid, 100 mg, 59% yield.

LCMS Rt 1.59 minutes. (ESI) m/z 536 [M³⁵ClH]⁺.

¹HNMR (d₆-DMSO): δ 6.81 (d, 1H), 7.46 (m, 2H), 7.57 (s, 1H), 7.92 (m,1H), 8.00 (m, 1H), 8.29 (s, 1H), 13.03 (brs, 1H).

Preparation 2475-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide

To a solution of N-(2,4-dimethoxybenzyl)-1,3,4-thiadiazol-2-amine(Preparation 248, 899 mg, 3.58 mmol) in tetrahydrofuran (6.0 mL), cooledto −78° C., was added lithium hexamethyldisilazide (1.0 M intetrahydrofuran, 4.3 mL) dropwise. The reaction was stirred for 35minutes at room temperature, cooled to −78° C. before the dropwiseaddition of 5-chloro-2,4-difluorobenzenesulfonyl chloride (850 mg,0.0034 mol). The reaction mixture was stirred at −78° C. for 1 hour thenat room temperature for 4 hours. The reaction mixture was poured intosaturated aqueous ammonium chloride solution and extracted withdichloromethane. The combined organic layers were washed with saturatedaqueous sodium chloride solution, dried over magnesium sulfate, filteredand concentrated in vacuo. The residue was purified by automated flashchromatography eluting with ethyl acetate:hexanes (gradient 0:1 to 1:0,by volume) to afford the title compound as a white solid, 1.16 g, 73%yield.

LCMS Rt=1.76 minutes. MS m/z 484 [M³⁵ClNa]+

¹HNMR (CDCl₃): δ 3.71 (s, 3H), 3.78 (s, 3H), 5.35 (m, 2H), 6.26 (m, 1H),6.38 (m, 1H), 6.99 (m, 1H), 7.27 (m, 1H), 7.83 (m, 1H), 8.87 (m, 1H).

Method 2

Preparation 247 can also be prepared as follows.

N-(2,4-Dimethoxybenzyl)-1,3,4-thiadiazol-2-amine (Preparation 248, 203.4g, 0.809 moles) was dissolved in 2-methyltetrahydrofuran (1.63 L) andthe yellow suspension was cooled to −38° C. to −45° C. Lithiumbis(trimethylsilyl)amide (890 mL of 1 molar solution in tetrahydrofuran,0.890 moles) was added slowly over 15 minutes keeping the temperaturebetween −38° C. and −45° C. to give an orange suspension. This orangesuspension was stirred at −38° C. to −45° C. for 45 minutes and then asolution of 5-chloro-2,4-difluorobenzenesulfonyl chloride, (200 g, 0.809moles) in 2-methyltetrahydrofuran (407 mL) was added slowly over 20minutes keeping the temperature between −38° C. and −45° C. to give anorange suspension. The mixture was stirred whist warming to 15° C. over1 hour. The reaction was quenched by adding a solution of ammoniumchloride (203.4 g, 3.80 moles) in water (1.02 L) and stirred vigorouslyfor 5 minutes. The stirring was stopped and the phases allowed toseparate. The lower layer was removed and the organic layer was washedwith water (813.6 mL). The organic layer was concentrated in vacuo togive an orange solid which was triturated with isopropyl acetate (1.22L) to give the title compound as a yellow-orange solid (218.6 g).

LC Rt=1.76 minutes. MS m/z 484 [M³⁵ClNa]+

¹HNMR (CDCl₃): δ 3.71 (s, 3H), 3.78 (s, 3H), 5.35 (m, 2H), 6.26 (m, 1H),6.38 (m, 1H), 6.99 (m, 1H), 7.27 (m, 1H), 7.83 (m, 1H), 8.87 (m, 1H).

Preparation 248 N-(2,4-Dimethoxybenzyl)-1,3,4-thiadiazol-2-amine

To a solution of 2-amino-1,3,4-thiadiazole (3.05 g, 0.0302 mol) and2,4-dimethoxy-benzaldehyde (4.55 g, 0.0274 mol) in dichloromethane (125mL) was added chlorotriisopropoxytitanium (16 mL, 0.067 mol) portionwiseover 5 minutes. After stirring for 1 hour, sodium triacetoxyborohydride(11.72 g, 0.05530 mol) was added portion wise and stirred for 24 hours.The reaction was quenched with saturated aqueous sodium bicarbonatesolution and adjusted to pH 9 with sodium hydroxide (6 N aqueoussolution) and extracted with dichloromethane. The combined organicextracts were dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by flash column chromatography elutingwith methanol:dichloromethane (gradient 0:1 to 1:9, by volume) to affordthe title compound as a white solid, 590 mg, 45% yield.

LCMS Rt=1.36 minutes. MS m/z 252 [MNa]+

¹HNMR (CDCl₃): δ 3.86 (s, 3H), 3.90 (s, 3H), 4.49 (m, 2H), 6.08 (br s,1H), 6.47 (m, 2H), 7.27 (m, 1H), 8.39 (s, 1H).

Method 2

Preparation 248 can also be prepared as follows.

2,4-Dimethoxybenzaldehyde (771.37 g, 4.64 moles) was added to asuspension of 2-amino-1,3,4-thiadiazole (391.2 g, 3.87 moles) in xylene(5.87 L) and heated to reflux. Dean-Stark apparatus was used to removethe water and the reaction was stirred overnight. After cooling to roomtemperature, the reaction was further cooled to 5° C. and diluted with2-methyltetrahydrofuran (2.93 L). Sodium tetrahydroborate (73.17 g, 1.93moles) was added as a single portion. Methanol (782.8 mL) was then addedslowly over 30 minutes, maintaining the temperature below 15° C. After afurther 30 minutes water (1 L) was added followed by saturated aqueoussodium hydrogencarbonate solution (1 L) and the mixture stirred at roomtemperature overnight. The biphasic mixture was diluted with2-methyltetrahydrofuran and heated to 43° C. to aid dissolution. Thelayers were separated and the organic layer washed with water (3 L)before concentrating in vacuo. The resulting solid was slurried inheptanes (2.5 L), homogenised, filtered, washed with tert-butylmethylether and dried to afford 715 g of the title compound.

LC Rt=1.36 minutes. MS m/z 252 [MNa]+

¹HNMR (d₆-DMSO): δ 3.75 (s, 3H), 3.80 (s, 3H), 4.37 (d, 2H), 6.49 (m,1H), 6.58 (s, 1H), 7.19 (d, 1H), 7.97 (m, 1H), 8.59 (s, 1H).

Preparation 250 tert-Butyl[(3-cyano-4-fluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate

To a stirred solution of tert-butyl 1,3-thiazol-4-ylcarbamate(Preparation 72, 0.500 g, 0.002497 mol) in tetrahydrofuran (10.0 mL) wasadded lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1.0 M solution intetrahydrofuran, 2.50 mL, 0.0025 mol) at 0° C. under nitrogen. Afterstirring for 1 hour at 0° C. the reaction mixture was cooled to −78° C.and 3-cyano-4-fluorobenzenesulfonyl chloride (0.453 g, 0.002063 mol) intetrahydrofuran (5.0 mL) was added. The mixture was warmed to roomtemperature for 16 hours. Saturated aqueous ammonium chloride solution(20.0 mL) was added and the aqueous layer was extracted with ethylacetate (3×20.0 mL). Combined organic layers were dried over sodiumsulfate and concentrated in vacuo. This crude residue was purified usingISCO™ (12 g SiO₂) eluting with ethyl acetate:dichloromethane (gradient0:1 to 3:7, by volume) to afford the title compound as a white solid,426 mg, 54% yield.

LCMS Rt=1.53 minutes MS m/z 284 [MH(-Boc)]+

1H NMR (400 MHz, d₆-DMSO): δ 1.25 (s, 9H), 7.90 (t, 1H), 8.15 (s, 1H),8.40 (m, 1H), 8.55 (d, 1H), 9.15 (s, 1H)

Preparation 255 tert-Butyl{[4-(4-chloro-2-iodophenoxy)-3-cyanophenyl]sulfonyl}1,3-thiazol-4-ylcarbamate

To a suspension of potassium carbonate (0.0549 g, 0.000397 mol) inN,N-dimethylformamide (3.0 mL) was added tert-butyl[(3-cyano-4-fluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation250, 0.1004 g, 0.000167 mol) and stirred at room temperature undernitrogen for 10 minutes. 4-chloro-2-iodophenol (0.067 g, 0.000263 mol)was added and stirred at room temperature for 16 hours. The reaction wasdiluted with ethyl acetate (10.0 mL). The organic phase was washedsaturated aqueous sodium chloride solution (2×10.0 mL), dried oversodium sulfate, filtered and concentrated in vacuo to afford the titlecompound as a yellow oil, 162 mg, 100% yield.

LCMS Rt=1.78 minutes MS m/z 618 [M³⁵ClH]+

¹H NMR (400 MHz, d₆-DMSO): δ 1.25 (s, 9H), 7.00 (d, 1H), 7.50 (d, 1H),7.65 (d, 1H), 7.90 (s, 1H), 8.10 (s, 1H), 8.20 (d, 1H), 8.55 (s, 1H),9.15 (s, 1H)

Preparation 258 2-(2-aminopyridin-4-yl)-4-chlorophenol

A suspension of 2-amino-4-chloropyridine (13 g, 101.12 mmol),(5-chloro-2-hydroxy)benzeneboronic acid (20.9 g, 121 mmol), tetrakistriphenylphosphine palladium (11.7 g, 10.1 mmol) and sodium carbonate(42.9 g, 404 mmol) in water (120 mL) and 1,4-dioxane (360 mL) was heatedto 90° C. under nitrogen for 24 hours. The reaction was cooled,concentrated in vacuo and the residue was extracted into ethyl acetate(500 mL) before filtration. The filtrate was washed with 2N HCl(aqueous, 500 mL) and water (700 mL). The combined aqueous layer wasbasified with saturated aqueous sodium bicarbonate solution (1500 mL)before extracting into ethyl acetate twice (2×800 mL). The organic layerwas dried over sodium sulphate and concentrated in vacuo. The residuewas purified using silica gel column chromatography (2-12% methanol indichloromethane) to afford the title compound as a yellow solid, 11.13g, 50%.

LCMS Rt=1.58 minutes. MS m/z 221 [M³⁵ClH]+

¹H NMR (400 MHz, d₆-DMSO): δ 5.80 (br s, 2H), 6.60 (m, 2H), 6.95 (m,1H), 7.20 (m, 1H), 7.90 (m, 1H), 9.95 (m, 1H).

Preparation 297 tert-Butyl1,3-thiazol-4-yl[(2,4,5-trifluorophenyl)sulfonyl]carbamate

To a solution of tert-butyl 1,3-thiazol-4-ylcarbamate (Preparation 72,28.94 g, 144.55 mmol) in anhydrous tetrahydrofuran (600 ml), cooled to−70° C., under nitrogen was added lithium1,1,1,3,3,3-hexamethyldisilazan-2-ide (1 M in tetrahydrofuran, 144.55ml, 144.55 mmol) dropwise. The reaction mixture was warmed to roomtemperature and stirred for 1 hour before cooling −70° C.2,4,5-trifluoro benzenesulfonyl chloride (40 g, 173.46 mmol) intetrahydrofuran (80 ml) was added dropwise and then the reaction mixturewas slowly warmed to room temperature and stirred for 2 hours. Thereaction mixture was quenched with saturated aqueous ammonium chloridesolution and extracted with ethyl acetate. Organic layer was washed withwater and saturated aqueous sodium chloride solution beforeconcentrating in vacuo. The crude residue was purified by columnchromatography eluting with ethyl acetate:hexane (gradient 1:19 to 3:17,by volume) to afford the title compound as white solid, 37 g, 64% yield.

LCMS Rt=3.46 minutes MS m/z 395 [MH]+

¹H NMR (400 MHz, CDCl₃): δ 1.35 (s, 9H), 7.07-7.13 (m, 1H), 7.52 (s,1H), 8.00-8.06 (m, 1H), 8.78 (s, 1H).

Preparation 3013-Cyano-4-fluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide

3-Cyano-4-fluorobenzenesulfonyl chloride (5 g, 20 mmol),5-fluoropyridin-2-amine (3.37 g, 30 mmol) and pyridine (4.87 mL, 60mmol) in dichloromethane (100 mL) were stirred at room temperature for 2hours before concentrating in vacuo. The residue was triturated inhydrochloric acid (2 N aqueous solution, 100 mL) for 16 hours. Theprecipitate was filtered to afford the title compound as a pale pinksolid, 6.1 g.

LCMS Rt=2.61 minutes, MS m/z 296 [MH]+.

1H NMR (400 MHz, d₆-DMSO): δ ppm 7.12 (dd, 1H), 7.62-7.79 (m, 2H), 8.19(d, 1H), 8.24-8.32 (m, 1H), 8.45 (dd, 1H), 11.42 (br. s., 1H).

Preparation 317 tert-Butyl4-[2-hydroxy-5-(trifluoromethyl)phenyl]piperidine-1-carboxylate

Boron tribromide (1 M in dichloromethane, 2.8 mL) was added to asolution of tert-butyl4-[2-methoxy-5-(trifluoromethyl)phenyl]piperidine-1-carboxylate(Preparation 318, 503 mg, 1.40 mmol) in dichloromethane (2 mL) at 0° C.and stirred for 1 hour at 0° C. and then at room temperature for 1 hour.The reaction mixture was quenched with cold water and basified to pH 9with saturated aqueous sodium bicarbonate solution. The aqueous layerwas extracted with ethyl acetate and organic extracts dried over sodiumsulfate, filtered and concentrated in vacuo to afford the intermediateas a light yellow solid.

LCMS Rt=1.23 minutes MS m/z 246 [MH]+

To the above crude intermediate (270 mg, 1.1 mmol) in acetonitrile (2.8mL) was added di-tert-butyldicarbonate (240 mg, 1.1 mmol) and stirred 18hours at room temperature before concentrating in vacuo. The residue waspurified via automated flash chromatography eluting with ethylacetate:hexanes (gradient 2:8 to 1:0, by volume) to afford the titlecompound as a white solid, 127 mg.

LCMS Rt=1.90 minutes MS m/z 246 [MH]+

Preparation 318 tert-Butyl4-[2-methoxy-5-(trifluoromethyl)phenyl]piperidine-1-carboxylate

tert-Butyl4-[2-methoxy-5-(trifluoromethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate(Preparation 319, 512 mg, 1.43 mmol) was hydrogenated for 16 hours overpalladium (10 wt. % on activated carbon, 10 mg, 0.009 mmol) at apressure of 40 psi. The reaction mixture was filtered through Celite™and concentrated in vacuo to afford the title compound as a white solid,503 mg.

LCMS Rt=2.03 minutes MS m/z 260 [MH]+

Preparation 319 tert-Butyl4-[2-methoxy-5-(trifluoromethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate

A suspension of 2-bromo-1-methoxy-4-(trifluoromethyl)benzene (825 mg,3.23 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(1.00 g, 3.23 mmol), potassium carbonate (1.34 g, 9.697 mmol) and[1,1-bis(diphenylphosphino)ferrocene]dichloro-palladium(11) complex withdichloromethane (1:1) (158 mg, 0.193 mmol) in N,N-dimethylformamide (19mL) was purged with argon. After 30 minutes, the reaction mixture washeated at 90° C. and stirred for 22 hours before cooling to roomtemperature and filtering through Celite™, washing with ethyl acetate.The filtrate was concentrated in vacuo to ˜quarter and partitionedbetween water (100 mL) and ethyl acetate (75 mL). The aqueous layer wasextracted with ethyl acetate (2×75 mL). Combined organic layers werewashed with water, aqueous lithium chloride solution, saturated aqueoussodium chloride solution, dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by automated flashchromatography (24 g silica gel) eluting with hexanes:ethyl acetate(gradient 1:0 to 3:1, by volume) to afford the title compound as a clearoil, 1.1 g.

LCMS Rt=1.71 minutes MS m/z 258 [MH]+

Preparation 322N-(5-Chloro-1,3-thiazol-2-yl)-4-(4-cyano-2-iodophenoxy)-2,5-difluorobenzenesulfonamide

To a suspension of potassium carbonate (0.068 g, 0.000492 mol) andN-(5-chloro-1,3-thiazol-2-yl)-N-(2,4-dimethoxybenzyl)-2,4,5-trifluorobenzenesulfonamide(Preparation 334, 0.200 g, 0.000418 mol) in dimethyl sulfoxide (3.0 mL)was added 4-hydroxy-3-iodobenzonitrile (Preparation 342, 0.108 g,0.000441 mol) and was stirred at 65° C. under nitrogen for 16 hours. Thereaction was diluted with ethyl acetate (10.0 mL). The organic phase waswashed with saturated aqueous sodium chloride solution (2×10.0 mL),dried over sodium sulfate, filtered and concentrated in vacuo. The crudewas dissolved in dichloromethane (1.5 mL), treated with trifluoroaceticacid (1.5 mL) and stirred at room temperature under nitrogen for 16hours. Reaction was concentrated in vacuo and residue dissolved in ethylacetate (10.0 mL). The organic extract was washed with saturated aqueoussodium bicarbonate solution (2×10.0 mL), dried over sodium sulphate,filtered and concentrated in vacuo. The resulting residue was purifiedusing ISCO™ (12 g SiO₂) eluting with methanol:dichloromethane (gradient0:1 to 1:39, by volume) to afford the title compound as an orange solid,165 mg, 35% yield.

LCMS Rt=1.60 minutes. MS m/z 552 [M³⁵ClH]+

Preparation 3335-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

To a solution of (N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine(Preparation 14, 40.6 g, 0.1619 mol) in anhydrous tetrahydrofuran (600.mL), cooled to −70° C., under nitrogen was added lithium1,1,1,3,3,3-hexamethyldisilazan-2-ide (1 M in tetrahydrofuran, 161.9 mL,0.161.9 mol) drop wise. The reaction mixture was warmed to roomtemperature and stirred for 1 hour before cooling to −70° C. A solutionof 5-chloro-2,4-difluorobenzenesulfonyl chloride (40 g, 0.1619 mol) intetrahydrofuran (200.0 mL) was added dropwise. After complete addition,the reaction mixture was gradually warmed to room temperature andstirred for 1 hour. Reaction mixture was quenched with saturated aqueousammonium chloride solution and extracted with ethyl acetate. Organiclayer was washed with water and saturated aqueous sodium chloridesolution. Crude residue was purified by column chromatography elutingwith ethyl acetate:hexane (gradient 1:19 to 3:17, by volume) to affordthe title compound as a white solid, 46 g.

LCMS Rt=3.88 minutes. MS m/z 462 [M³⁵ClH]+

1H NMR (400 MHz, CDCl₃): δ 3.66 (s, 3H), 3.74 (s, 3H), 5.34 (s, 2H),6.14-6.15 (m, 2H), 6.34 (dd, 1H), 6.86 (t, 1H), 7.19 (d, 1H), 7.73 (t,1H), 8.21 (s, 1H)

Preparation 334N-(5-Chloro-1,3-thiazol-2-yl)-N-(2,4-dimethoxybenzyl)-2,4,5-trifluorobenzenesulfonamide

Prepared according to Preparation 333 using5-chloro-N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 208)and 2,4,5-trifluorobenzenesulfonyl chloride. Purification using ISCO™(12 g SiO₂) eluting with ethyl acetate:heptane (gradient 0:1 to 3:7, byvolume) afforded the title compound as an orange solid.

LCMS Rt=1.80 minutes. MS m/z 479 [M³⁵ClH]+

¹H NMR (400 MHz, CDCl₃): δ 3.70 (s, 3H), 3.75 (s, 3H), 5.15 (s, 2H),6.18 (d, 1H), 6.35 (m, 1H), 6.87 (m, 1H), 7.20 (d, 1H), 7.77 (m, 1H),8.22 (s, 1H)

Preparation 3371-(Ethoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Butyl lithium (2.5 M in hexanes, 32.4 mL, 0.0811 mol) was added slowlyvia syringe to a solution of 1-(ethoxymethyl)-1H-pyrazole (Preparation338, 9.3 g, 0.074 mol) in anhydrous tetrahydrofuran (100.0 mL) at 0° C.and stirred under nitrogen for 15 minutes and then at room temperaturefor 30 minutes. The mixture was cooled to −78° C. and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (16.5 mL, 0.0811mol) was added via syringe. The mixture was warmed to room temperatureand stirred under nitrogen for 60 hours. Saturated aqueous ammoniumchloride solution (50.0 mL) was added followed by water (150.0 mL). Themixture was poured into tert-butylmethylether (200.0 mL) and thebiphasic mixture stirred vigorously for 30 minutes. The aqueous layerwas acidified to pH 6 with hydrochloric acid (6.0 M aqueous solution)and extracted with tert-butylmethylether (3×200.0 mL). The combinedorganics were washed with saturated aqueous sodium chloride solution(100.0 mL) and then stirred with activated charcoal (1 g) for 30minutes. Magnesium sulphate was added and the mixture filtered through apad of Celite™, washing with tert-butylmethylether (1 L). Concentrationin vacuo afforded the title compound as a brown oil, 14.5 g, 78% yield.

¹H NMR (400 MHz, CDCl₃): δ 1.14 (t, 3H) 1.34 (s, 12H) 3.52 (q, 2H) 5.71(s, 2H) 6.78 (d, 1H) 7.58 (d, 1H).

Preparation 338 1-(Ethoxymethyl)-1H-pyrazole

To a mixture of pyrazole (10 g, 0.150 mol) and potassium carbonate (22.3g, 0.162 mol) in acetone (200.0 mL), cooled to 0° C. under nitrogen, wasadded chloromethyl ethyl ether (15.0 mL, 0.162 mol) via syringe over aperiod of 20 minutes. The reaction was stirred for 30 minutes at 0° C.and then for 2 hours at room temperature. The mixture was filtered,washing the solid with acetone (200.0 mL). The filtrate was carefullyconcentrated in vacuo (at 400 mbar). The crude material was purified byflash column chromatography eluting with pentane:diethylether (1:1, byvolume) to afford the title compound as a colourless oil, 9.3 g, 50%yield.

¹H NMR (400 MHz, CDCl₃): δ 1.18 (t, 3H) 3.54 (q, 2H) 5.47 (s, 2H) 6.35(t, 1H) 7.57 (d, 1H) 7.59 (d, 1H).

Preparation 339 4-(5-Chloro-2-hydroxyphenyl)pyridine-2-carbonitrile

(5-Chloro-2-hydroxyphenyl)boronic acid (2.0 g, 0.012 mol),4-chloropyridine-2-carbonitrile (1.61 g, 0.012 mol),(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (0.424 g,0.00058 mol) and sodium carbonate (3.7 g, 0.035 mol) in 1,4-dioxane(20.0 mL) and deionised water (1.0 mL) were degassed with nitrogen (×3)before heating at 100° C. for 18 hours under nitrogen. The reaction wascooled and hydrochloric acid (2.0 M aqueous solution, 30.0 mL) added.Reaction was filtered, washing with ethyl acetate (50.0 mL). The organiclayer was concentrated in vacuo and purified by flash columnchromatography on the ISCO™ (40 g SiO₂) eluting with ethylacetate:heptane (gradient 0:1 to 7:3, by volume) to afford the titlecompound as a yellow solid, 0.23 g, 8.6% yield.

LCMS Rt=1.42 minutes. MS m/z 231.0 [M³⁵ClH]+

¹H NMR (400 MHz, d₆-DMSO): δ 7.01 (d, 1H), 7.33 (dd, 1H), 7.54 (d, 1H),7.97 (dd, 1H), 8.23 (m, 1H), 8.74 (m, 1H)

Preparation 3405-Chloro-4-[4-chloro-2-(2-cyanopyridin-4-yl)phenoxy]-N-(2,4-dimethoxybenzyl)-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

Prepared according to Preparation 255 using4-(5-chloro-2-hydroxyphenyl)pyridine-2-carbonitrile (Preparation 339,0.23 g, 0.001 mol) and5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 333, 461 mg, 0.998 mmol). Saturated aqueous sodium chloridesolution (20.0 mL) was added to the reaction resulting in the formationof a white precipitate. This was filtered and washed with water (20.0mL) and heptane (20.0 mL) before being dried in vacuo for 2 hours toafford the title compound as a white solid, 0.67 g, 100% yield.

LCMS Rt=3.87 minutes. MS m/z 694.0 [M³⁵ClH]+

¹H NMR (400 MHz, d₆-DMSO): δ 3.58 (s, 3H), 3.66 (s, 3H), 5.20 (s, 2H),6.20 (m, 1H), 6.40 (m, 1H), 7.05 (m, 2H), 7.22 (m, 1H), 7.65 (m, 2H),7.82 (d, 1H), 7.85 (dd, 1H), 8.20 (dd, 1H), 8.42 (d, 1H), 8.77 (dd, 1H)

Preparation 341 4-(Difluoromethoxy)-2-iodophenol

To a suspension of N-iodosuccinimide (1.12 g, 0.005 mol) in acetic acid(15.0 mL) was added 4-(difluoromethoxy)phenol (0.8 g, 0.005 mol) undernitrogen. Sulfuric acid (0.147 g, 0.0015 mol) was added and theresulting dark brown suspension was stirred at room temperature for 4hours before the addition of N-iodosuccinimide (0.6 g, 0.0025 mol). Themixture was stirred for 16 hours before diluting with citric acid (1.0 Maqueous solution, 20.0 mL) and water (20.0 mL). The aqueous layer wasextracted with dichloromethane (2×30.0 mL). Combined organic layers weredried over sodium sulphate, filtered and concentrated in vacuo to afforda dark purple oil. This was concentrated in vacuo from toluene (3×20.0mL) to afford a brown oil. The aqueous layer was concentrated in vacuo.Both organic and aqueous crude residues were purified by flash columnchromatography on the ISCO™ (40 g SiO₂) eluting with ethylacetate:heptane (gradient 0:1 to 1:1, by volume) to afford the titlecompound as a yellow oil, 0.604 g, 42% yield.

LCMS Rt=1.44 minutes. MS m/z 285.0 [MH]−

¹H NMR (400 MHz, CDCl₃): δ 6.40 (t, 1H), 6.97 (d, 1H), 7.07 (dd, 1H),7.46 (d, 1H)

Preparation 342 4-Hydroxy-3-iodobenzonitrile

4-Hydroxy-3-iodobenzonitrile was prepared by the method analogous toPreparation 341 above using N-iodosuccinimide, acetic acid, sulfuricacid and 4-Hydroxybenzonitrile. Purified by ISCO™ (80 g SiO₂) elutingwith ethyl acetate:heptane (gradient 0:1 to 3:7, by volume) to yield thetitle compound.

LCMS Rt=1.28 minutes

MS m/z 244 [MH]−

¹H NMR (400 MHz, d₆-DMSO): δ 6.95 (d, 1H), 7.65 (d, 1H), 8.15 (s, 1H),11.50 (s, 1H)

Preparation 3495-Chloro-2,4-difluoro-N-(5-fluoropyridin-2-yl)-N-(methoxymethyl)benzenesulfonamide

5-Chloro-2,4-difluorobenzenesulfonyl chloride (1 g, 4 mmol) indichloromethane (7.6 mL) was added portion-wise to a solution of2-amino-5-fluoropyridine (498 mg, 4.44 mmol) in pyridine (7.6 mL, 94mmol) cooled to 0° C. After addition was complete, the reaction mixturewas warmed to room temperature. After 16 hours, the reaction mixture wasdiluted with dichloromethane and hydrochloric acid (1 N aqueoussolution). The aqueous layer was extracted with dichloromethane. Thecombined organic layers were washed with water, diluted with ethylacetate, dried over sodium sulfate, filtered and concentrated in vacuo.The residue was dissolved in dichloromethane (8.0 mL) andN,N-diisopropylethylamine (0.776 mL, 4.45 mmol) added. The mixture wascooled to 0° C. and chloromethyl methyl ether (0.338 mL, 4.45 mmol) wasadded dropwise by syringe. The reaction mixture was warmed to roomtemperature and after stirring for 6 hours, the reaction mixture wasdiluted with dichloromethane and washed with saturated aqueous sodiumbicarbonate solution. The organic layer was dried over sodium sulfate,filtered and concentrated in vacuo onto Celite™. The residue waspurified by automated flash chromatography (24 g silica gel column)eluting with ethyl acetate:hexanes (gradient 0:1 to 1:0, by volume) toafford the title compound, 363 mg.

LCMS Rt=1.78 minutes. MS m/z 367 [MH]+

Preparation 3554-(4-Chloro-2-iodophenoxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

Prepared according to Preparation 50 using 4-chloro-2-iodophenol.

¹H NMR (400 MHz, d₆-DMSO) δ 6.86 (d, 1H), 7.42 (d, 1H), 7.61 (dd, 1H),7.99 (dd, 1H) 8.08 (d, 1H) 8.31 (d, 1H) 8.48 (s, 1H) ppm.

Preparation 363N-(2,4-Dimethoxybenzyl)-2,5-difluoro-4-[2-iodo-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

Prepared according to Preparation 255 usingN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 647, 1000 mg, 2.26 mmol) and2-iodo-4-(trifluoromethyl)phenol (Preparation 224, 975 mg, 3.38 mmol) toafford the title compound, 1080 mg, 67% yield.

LCMS Rt=4.14 minutes.

¹H NMR (d₆-DMSO): δ 3.60 (s, 3H), 3.70 (s, 3H), 5.20 (s, 2H), 6.40 (m,2H), 7.05 (m, 1H), 7.30 (m, 2H), 7.80 (m, 2H), 8.30 (s, 1H), 8.45 (s,1H).

Preparation 3693-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazole

3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(7.4 g, 0.0356 mol), 1,1′,1″-(chloromethanetriyl)tribenzene (9.9 g,0.0356 mol) and triethylamine (7.2 g, 0.0712 mol) were suspended inN,N-dimethylformamide (70.0 mL) and stirred at room temperature for 16hours. The reaction mixture was quenched by addition of water (30.0 mL)and extracted with ethyl acetate (3×30.0 mL). The combined organiclayers were washed with saturated aqueous sodium chloride solution (40.0mL), dried over sodium sulfate and concentrated in vacuo. This cruderesidue was initially purified via column chromatography eluting withpetroleum ether:ethyl acetate (10:1, by volume) and then purified bypreparative HPLC to yield title compound as a white solid.

¹H NMR (400 MHz, CDCl₃): δ 1.25 (s, 12H), 2.32 (s, 3H), 7.06 (m, 6H),7.20 (m, 9H), 7.52 (s, 1H).

Preparation 403 (1-Methyl-1H-pyrazol-5-yl)boronic acid

To a stirred solution of 1-methyl-1H-pyrazole (2.49 mL, 30 mmol) intetrahydrofuran (100 mL) was added butyllithium (2.5 M in hexane, 15.6mL, 39 mmol) at −78° C. dropwise. After stirring for 1 hour,triisopropyl borate (27.6 mL, 120 mmol) was added and the reactionmixture was gradually warmed to room temperature for 16 hours.Hydrochloric acid (1 N aqueous solution) was added to the reactionmixture until pH 7 achieved. The mixture was extracted withdichloromethane:methanol (9:1, 5×200 mL). Combined organic extracts weredried over magnesium sulphate and concentrated in vacuo to obtain cruderesidue. Purification was undertaken by flash column chromatography(ISCO™) eluting with dichloromethane:methanol (7:3, by volume) to affordthe title compound as a white solid, 1258 mg, 33% yield.

¹H NMR (400 MHz, CD₃OD): δ 3.99 (s, 3H), 6.66 (d, 1H), 7.42-7.51 (m, 1H)ppm.

Preparation 4083-Cyano-4-[2-iodo-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

To a suspension of potassium carbonate (0.850 g, 0.006150 mol) and3-cyano-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation65, 0.500 g, 0.001759 mol) in dimethyl sulfoxide (5.0 mL) was added2-iodo-4-(trifluoromethyl)phenol (Preparation 224, 0.595 g, 0.002066mol) and stirred at 80° C. under nitrogen for 16 hours. The reactionmixture was diluted with ethyl acetate (10.0 mL) and the organic phasewas washed with saturated aqueous sodium chloride solution (2×10.0 mL),dried over sodium sulphate, filtered and concentrated in vacuo. Theresidue was triturated in ethyl acetate (5.0 mL) to yield title compoundas a white solid, 560 mg, 58% yield.

LCMS Rt=1.75 minutes MS m/z 553 [MH]+

1H NMR (400 MHz, d₆-DMSO): δ 6.90 (d, 1H), 7.45 (d, 1H), 7.85 (m, 2H),7.95 (d, 1H), 8.10 (s, 1H), 8.30 (s, 1H)

Preparation 419N-{1-tert-Butyl-4-[5-chloro-2-(2-cyano-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-ynamino]sulfonyl}phenoxy)phenyl]-1H-pyrazol-5-yl}-2,2,2-trifluoroacetamide

To a solution of3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 68, 150 mg, 0.35 mmol) in dimethyl sulfoxide (10 ml) wasaddedN-[1-tert-butyl-4-(5-chloro-2-hydroxyphenyl)-1H-pyrazol-5-yl]-2,2,2-trifluoroacetamide(Preparation 209, 131 mg, 0.36 mmol) and potassium carbonate (135 mg,0.86 mmol) and the flask was purged with nitrogen (×3). The resultingsuspension was stirrd at room temperature for 18 hours before pouringinto sodium hydroxide (1 M aqueous solution) and extracting withdichloromethane. The combined organic phase was dried over magnesiumsulfate, filtered and concentrated in vacuo to afford a pale yellow oil.This was purified by column chromatography (80 g silica gel column)eluting with ethyl acetate:heptane (1:1, by volume) to furnish the titlecompound as a pale yellow oil, 157 mg, 59% yield.

LCMS Rt=4.88 minutes.

¹H NMR (CDCl₃, 400 MHz): δ 1.63 (s, 9H), 3.52 (s, 3H), 3.80 (s, 3H),5.26 (s, 2H), 6.12 (s, 1H), 6.33-6.38 (m, 1H), 6.54-6.59 (m, 1H),7.04-7.10 (m, 2H), 7.37-7.42 (m, 1H), 7.45 (s, 1H), 7.49 (s, 1H),7.66-7.72 (m, 2H), 8.18 (s, 1H), 8.30 (s, 1H).

Preparation 4243-Cyano-N-(2,4-dimethoxybenzyl)-4-{2-[1-(ethoxymethyl)-1H-pyrazol-5-yl]-4-(trifluoromethoxy)phenoxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

Prepared according to Method U (below) using1-(ethoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Preparation 337, 197 mg, 0.714 mmol), and3-cyano-N-(2,4-dimethoxybenzyl)-4-[2-iodo-4-(trifluoromethoxy)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 497, 210 mg, 0.42 mmol). The material was purified bycolumn chromatography eluting with ethyl acetate:heptane (1:1, byvolume) to furnish the title compound as a white solid, 70 mg, 29%yield.

LCMS Rt=3.71 minutes

¹H NMR (d₆-DMSO): δ 1.00 (m, 3H), 3.40 (m, 2H), 3.80 (m, 6H), 5.05 (s,2H), 5.40 (s, 2H), 6.40 (m, 2H), 6.50 (m, 1H), 6.80 (m, 1H), 7.20 (m,1H), 7.40 (m, 2H), 7.60 (m, 1H), 7.70 (m, 1H), 7.80 (m, 1H), 8.00 (m,1H), 8.35 (m, 1H).

Method U

Example 771 was prepared using Method U below.

To a solution ofN-(5-chloro-1,3-thiazol-2-yl)-4-(4-cyano-2-iodophenoxy)-2,5-difluorobenzenesulfonamide(Preparation 322, 0.160 g, 0.000200 mol) in 1,4 dioxane (3.0 mL) andwater (1.0 mL) was added caesium carbonate (0.165 g, 0.000506 mol),palladium tetrakis triphenylphosphine (0.0023 g, 0.000020 mol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.0784 g,0.000404 mol) and stirred at 85° C. under nitrogen for 16 hours. Thereaction was diluted with ethyl acetate (10.0 mL) and the organic phasewashed saturated aqueous sodium chloride solution (2×10.0 mL), driedover sodium sulphate, filtered and concentrated in vacuo. Purificationby preparative HPLC afforded the title compound.

LCMS Rt=3.18 minutes MS m/z 494 [M³⁵ClH]+

Preparation 426 3-Chloro-4-fluoro-N-pyrimidin-4-ylbenzenesulfonamide

4-Aminopyrimidine (1.0 g, 10.5 mmol) and DABCO™ (1.18 g, 10.5 mmol) wereadded concurrently to a solution of 3-chloro-4-fluorobenzenesulfonylchloride (1.25 mL, 10.0 mmol) in anhydrous acetonitrile (49 mL). Thereaction mixture immediately turned yellow and a precipitate was formed.After stirring for 16 hours, the mixture was concentrated in vacuo. Thecrude material was suspended in ethyl acetate (75 mL) and water (75 mL)and stirred for 15 minutes. The resulting solid was filtered and driedin vacuo to afford the title compound, 0.83 g, 27% yield.

LCMS Rt=1.31 minutes MS m/z 288 [MH]+

¹HNMR (300 MHz, d₆-DMSO): δ 6.90-7.00 (1H, m), 7.63 (1H, t), 7.91-7.96(1H m), 8.28 (1H, s), 8.07-88.10 (1H, m), 8.64 (1H, s), 13.05 (1H, brs).

Preparation 4283-Cyano-4-[2-(5-methyl-1-trityl-1-pyrazol-4-yl)-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

Prepared according to Preparation 211 using3-cyano-4-[2-iodo-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 408) and3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-pyrazole(Preparation 369). Purified by silica gel chromatography (ISCO™ 12 gSiO₂) eluting with dichloromethane:(methanol:acetic acid 10:1, byvolume) (gradient 1:0 to 95:5, by volume) to afford the title compound.

LCMS Rt=4.91 minutes

¹H NMR (400 MHz, d₆-DMSO): δ 2.20 (s, 3H), 6.75 (d, 1H), 6.90 (m, 6H),7.20 (d, 1H), 7.25-7.30 (m, 9H), 7.55 (d, 1H), 7.80-7.90 (m, 3H), 8.20(d, 1H), 8.45 (s, 1H)

Preparation 4293-Cyano-N-(2,4-dimethoxybenzyl)-4-[2-iodo-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

Prepared according to Method O (below) at room temperature using3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 68) and 2-iodo-4-(trifluoromethyl)phenol (Preparation 224).The title compound was isolated as a white solid.

¹HNMR (400 MHz, d₆-DMSO): δ 3.60 (s, 3H), 3.75 (s, 3H), 5.20 (s, 2H),6.45 (m, 2H), 6.90 (d, 1H), 7.05 (d, 1H), 7.55 (d, 1H), 7.90 (d, 1H),8.05 (d, 1H), 8.25 (s, 1H), 8.35 (s, 1H), 8.40 (s, 1H)

Method O

Example 765 was prepared as follows.

To a solution of tert-butyl4-(5-chloro-2-hydroxyphenyl)piperidine-1-carboxylate (Preparation 231,37.1 mg, 0.119 mmol) in dimethyl sulfoxide (2 mL) was added potassiumcarbonate (22.4 mg, 0.162 mmol) and5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide(Preparation 247, 50.0 mg, 0.108 mmol). The resulting mixture was heatedto 50° C. for 30 minutes. After cooling, the reaction was diluted withethyl acetate and water. The layers were separated and the aqueous layerextracted with ethyl acetate. The combined organic extracts were washedwith saturated aqueous sodium chloride solution and water, dried overmagnesium sulphate and concentrated in vacuo. The residue was purifiedby automated flash column chromatography using an ISCO™ (12 g column)eluting with ethyl acetate:hexanes (gradient 0:1 to 1:1, by volume). Thefully protected intermediate was taken up in dichloromethane (2 mL) andtrifluoroacetic acid (83.4 uL, 1.08 mmol) was added. The resultingmixture was stirred at room temperature. After 16 hours, the reactionwas concentrated in vacuo and purified by preparative HPLC eluting withacetonitrile:water (gradient 15:85 to 1:0, by volume) to afford thetrifluoroacetic acid salt of the title compound as a white solid, 26 mg,39% yield.

LCMS Rt=1.47 minutes. MS m/z 503 [M³⁵ClH]+

¹H NMR (d₆-DMSO): δ 1.80 (m, 4H), 2.94 (m, 3H), 3.31 (m, 2H), 7.03 (m,2H), 7.35 (m, 2H), 7.96 (d, 1H), 8.83 (s, 1H).

Method 2

Preparation 429 can also be prepared as follows.

To a solution of3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 68, 25 g, 57.5 mmol) in DMSO (125 mL) was added potassiumcarbonate (20.4 g, 148 mmol) followed by dropwise addition of the2-iodo-4-(trifluoromethyl)phenol (Preparation 224, 17.4 g, 60.6 mmol).The reaction was stirred at room temperature for 2 hours. The reactionwas poured into water (1 L) and extracted with ethyl acetate (3×300 mL).The organic layers were combined and washed with water (2×250 mL), driedover sodium sulfate and concentrated in vacuo. The residue was slurriedin methanol (150 mL) for 1 hour before filtering and drying under vacuumto afford 33.92 g of the title compound as a white solid (83%).

¹HNMR (400 MHz, d₆-DMSO): δ 3.60 (s, 3H), 3.75 (s, 3H), 5.20 (s, 2H),6.45 (m, 2H), 6.90 (d, 1H), 7.05 (d, 1H), 7.55 (d, 1H), 7.90 (d, 1H),8.05 (d, 1H), 8.25 (s, 1H), 8.35 (s, 1H), 8.40 (s, 1H).

Preparation 453 tert-Butyl[(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate

To a solution of thiazol-4-yl-carbamic acid tert-butyl ester(Preparation 72, 503 mg, 0.00251 mol) in tetrahydrofuran (5.0 mL) cooledto −78° C. was added lithium hexamethyldisilazide (1.0 M intetrahydrofuran, 2.76 mL, 0.00276 mol). The reaction was stirred for 30minutes at room temperature and then cooled to −78° C. A solution of5-chloro-2,4-difluorobenzenesulfonyl chloride (620.5 mg, 0.002512 mol)in tetrahydrofuran (5.0 mL) was added slowly via syringe. After additionwas complete, the reaction mixture remained immersed in the coolingbath; the temperature of the dry ice bath was not maintained, allowingthe reaction mixture to slowly warm to room temperature. After 24 hours,the reaction mixture was poured into saturated aqueous ammonium chloridesolution and extracted with ethyl acetate. The combined organic extractswere dried over magnesium sulfate, filtered and concentrated in vacuoonto Celite™. The residue was purified by automated flash chromatography(40 g SiO₂) eluting with ethyl acetate:dichloromethane (gradient 0:1 to5:95, by volume) to afford the title compound as a white solid, 733 mg,71% yield.

LCMS Rt=1.70 minutes. MS m/z 311 [M³⁵Cl(-Boc)H]⁺

1H NMR (300 MHz, d₆-DMSO): δ 1.40 (s, 9H), 7.10 (m, 1H), 7.52 (m, 1H),8.25 (t, 1H), 8.80 (m, 1H) ppm.

Preparation 4973-cyano-N-(2,4-dimethoxybenzyl)-4-[2-iodo-4-(trifluoromethoxy)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

The title compound was prepared according to Preparation 255 using2-iodo-4-(trifluoromethoxy)phenol (Preparation 226) and3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 68).

¹HNMR (CDCl₃): δ 3.65 (s, 1H), 3.80 (s, 3H), 5.38 (s, 2H), 6.25 (m, 1H),6.37 (m, 1H), 6.50 (m, 1H), 7.10 (m, 2H), 7.35 (m, 1H), 7.8 (m, 3H), 8.2(s, 1H).

Preparation 533 2-(1-Methyl-1H-pyrazol-5-yl)-4-(trifluoromethoxy)phenol

A solution of5-[2-(benzyloxy)-5-(trifluoromethoxy)phenyl]-1-methyl-1H-pyrazole(Preparation 534, 2.3 g, 6.6 mmol) in methanol (25 mL) was degassed withargon before the addition of palladium on carbon (10%, 230 mg). Reactionmixture was stirred at room temperature under hydrogen atmosphere (usinga balloon) for 16 hours. After filtration through Celite™, filtrate wasconcentrated in vacuo to afford the title compound as a white solid, 1.6g, 94% yield.

¹H NMR (400 MHz, d₆-DMSO): δ 3.68 (s, 3H), 6.28 (d, 1H), 7.04 (d, 1H),7.18 (s, 1H), 7.28-7.30 (m, 1H), 7.44 (d, 1H), 10.36 (br s, 1H) ppm.

Preparation 5345-[2-(Benzyloxy)-5-(trifluoromethoxy)phenyl]-1-methyl-1H-pyrazole

A solution of 1-(benzyloxy)-2-bromo-4-(trifluoromethoxy)benzene(Preparation 535, 3.3 g, 9.5 mmol) and (1-methyl-1H-pyrazol-5-yl)boronicacid (Preparation 403, 1.2 g, 9.5 mmol) 1,4-in dioxane (25 mL) wasdegassed under argon for 30 minutes. Under argon,(1E,4E)-1,5-Diphenylpenta-1,4-dien-3-one-palladium (3:2) (348 mg, 0.38mmol) and tricyclohexylphosphine (213 mg, 0.76 mmol) were added followedby the dropwise addition of a degassed solution of tripotassiumphosphate (4 g, 19 mmol) in water (12.6 mL). Reaction mixture wasrefluxed for 16 hours before cooling to room temperature and filteringthrough Celite™. The filtrate was concentrated in vacuo and the residuewas diluted with ethyl acetate (100 mL). The organic extract was washedwith water, saturated aqueous sodium chloride solution, dried oversodium sulfate and concentrated in vacuo. Purification by silica gelcolumn chromatography eluting with ethyl acetate:hexane (1:9, by volume)afforded the title compound, 2.3 g, 70% yield.

1H NMR (400 MHz, d₆-DMSO): δ 3.64 (s, 3H), 5.18 (s, 2H), 6.33 (s, 1H),7.32-7.51 (m, 9H) ppm.

Preparation 535 1-(Benzyloxy)-2-bromo-4-(trifluoromethoxy)benzene

To a suspension of 2-bromo-4-(trifluoromethoxy)phenol (3 g, 11.7 mmol)and potassium carbonate (3.23 g, 23.4 mmol) in N,N-dimethylformamide (35mL) was added benzyl bromide (2.1 mL, 17.5 mmol) dropwise and stirred atroom temperature for 16 hours. Reaction mixture was diluted with ethylacetate and washed with water, saturated aqueous sodium chloridesolution, dried over sodium sulfate, filtered and concentrated in vacuo.Purification by silica gel column chromatography eluting with ethylacetate:hexane (2:98, by volume) afforded the title compound, 3.3 g, 81%yield.

¹H NMR (400 MHz, CDCl₃): δ 5.14 (s, 2H), 6.90 (d, 1H), 7.10 (d, 1H),7.31-7.46 (m, 6H) ppm.

Preparation 647N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

To a solution of (N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine(Preparation 14, 13 g, 51.73 mmol) in dry tetrahydrofuran (150 ml) at−70° C. under argon atmosphere was added 1 M lithium1,1,1,3,3,3-hexamethyldisilazan-2-ide in tetrahydrofuran (56.9 ml, 56.9mmol) dropwise. The reaction mixture was allowed to warm up to roomtemperature and stirred for 1 h. It was again cooled to −70° C. and atetrahydrofuran (50 ml) solution of 2,4,5-trifluorobenzenesulfonylchloride (11.9 g, 51.73 mmol) was added dropwise to it at thistemperature. After complete addition, reaction mixture was graduallyallowed to warm up to room temperature and stirred for 1 hour. Thereaction mixture was quenched with saturated aqueous ammonium chloridesolution and extracted with ethyl acetate. The organic layer was washedwith water and saturated aqueous sodium chloride solution. Crude productwas purified over 100-200 silica gel using 5-15% v/v ethyl acetate inhexane to give 17 g (75%) of the title compound as a white solid.

LCMS Rt=3.85 minutes MS m/z 446 [MH]+

¹HNMR (CDCl₃): δ 3.68 (s, 3H), 3.74 (s, 3H), 5.32 (s, 2H), 6.20 (m, 1H),6.34 (m 1H), 6.90 (m, 1H), 7.17 (d, 1H), 7.56-7.62 (m, 1H), 8.19 (s,1H).

Preparation 6533-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

Prepared according to Preparation 207 using(2,4-dimethoxybenzyl)-[1,2,4]thiadiazol-5-yl-amine (Preparation 14) and3-chloro-4-fluorobenzenesulfonyl chloride.

¹HNMR (d₆-DMSO): δ 3.63 (s, 3H), 3.71 (s, 3H), 5.21 (s, 2H), 6.38-6.44(m, 2H), 7.00 (m, 1H), 7.61 (m, 1H) 7.85-7.93 (m, 2H), 8.41 (s, 1H).

Preparation 6555-chloro-N-(5-chloro-1,3-thiazol-2-yl)-N-(2,4-dimethoxybenzyl)-2,4-difluorobenzenesulfonamide

Prepared according to Preparation 207 using5-chloro-N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 208)and 5-chloro-2,4-difluorobenzenesulfonyl chloride.

LCMS Rt=1.84 minutes MS m/z 495 [M³⁵ClH]+

Preparation 669 tert-butyl4-[5-chloro-2-(2-chloro-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}phenoxy)phenyl]-1H-pyrazole-1-carboxylate

tert-butyl 4-(5-chloro-2-hydroxyphenyl)-1H-pyrazole-1-carboxylate(Preparation 205, 99.6 mg, 0.338 mmol),3-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 653, 153 mg, 0.345 mmol) and potassium carbonate (59.8 mg,0.433 mmol) were stirred in dimethylsulphoxide (5 ml) at roomtemperature for 16 hours. The mixture was diluted with saturated aqueoussodium chloride solution (40 ml) and extracted with ethyl acetate (3×40ml). The combined organics were dried over anhydrous magnesium sulphate,filtered and the solvents removed in vacuo to give the crude productwhich was purified by column chromatography using the ISCO® (using agradient of 0-40% v/v ethyl acetate in heptane, 12 g SiO₂) to give thetitle compound as a white solid (121 mg)

LCMS Rt=1.94 minutes, MS m/z 616 [³⁵ClM−BocH]⁻ and 618 [³⁷ClMH−Boc]⁻

¹HNMR (CDCl₃): δ 1.65 (s, 9H), 3.67 (s, 3H), 3.76 (s, 3H), 5.27 (s, 2H),6.28 (s, 1H), 6.35 (d, 1H), 6.60 (d, 1H), 6.94 (d, 1H), 7.08 (d, 1H),7.31 (dd, 1H), 7.48 (dd, 1H), 7.64 (s, 1H), 7.75 (s, 1H), 8.03 (s, 1H),8.18 (s, 1H), 8.44 (s, 1H)

Preparation 679 tert-butyl({4-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy]-3-cyanophenyl}sulfonyl)1,3-thiazol-4-ylcarbamate

tert-butyl{[4-(4-chloro-2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}phenoxy)-3-cyanophenyl]sulfonyl}1,3-thiazol-4-ylcarbamate,(Preparation 680, 224 mg, 0.287 mmol) was dissolved in dichloromethane(10 ml) and N,N,N′,N′-tetramethylnaphthalene-1,8-diamine (150 mg, 0.70mmol) was added, followed by 1-chloroethyl chloroformate (0.07 ml, 0.65mmol) and the solution was stirred at room temperature for 3.5 hours.Concentrated in vacuo and the residue was dissolved in methanol (10 ml)and refluxed for 4 hours. Concentrated in vacuo to give the crude titlecompound as a brown gum, 200 mg. This material was used withoutpurification in Example 815.

Preparation 680 tert-Butyl{[4-(4-chloro-2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}phenoxy)-3-cyanophenyl]sulfonyl}1,3-thiazol-4-ylcarbamate

4-chloro-2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}phenol,(Preparation 689, 75 mg, 0.18 mmol), tert-butyl[(3-cyano-4-fluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation250, 69 mg, 0.18 mmol), potassium carbonate (62 mg, 0.45 mmol) anddimethyl sulphoxide (4 ml) were combined and stirred at room temperatureunder nitrogen for 4 hours. Saturated aqueous ammonium chloride solution(20 ml) was added and the mixture extracted with ethyl acetate (1×20ml). The organic layer was separated and back-washed with saturatedaqueous sodium chloride solution

(2×20 ml). The organic layer was separated, dried over sodium sulphate,filtered and evaporated to give an oil. The oil was purified using anISCO® Companion (4 g. silica gel, gradient from dichloromethane todichloromethane:methanol 98:2). The appropriate fractions were combinedand solvents removed in vacuoto give the title compound as a glass. Yield 33 mg. 24%.

LCMS Rt=1.48 minutes, m/z 779 [M³⁵ClH]+

¹HNMR (CDCl₃): δ 1.32 (s, 9H), 3.59 (m, 2H), 3.67 (m, 2H), 4.57 (s, 1H)4.90 (m, 1H), 6.21 (s, 1H) 6.87 (d, 1H) 7.35 (m, 15H), 8.10 (d, 1H),8.31 (s, 1H), 8.59 (s, 1H).

TLC Rf=0.5 (dichloromethane:methanol 98:2)

Preparation 6815-chloro-N-(2,4-dimethoxybenzyl)-4-(2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}-4-fluorophenoxy)-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

Prepared by analogy to Preparation 680 from2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}-4-fluorophenol(Preparation 682, 249 mg, 0.623 mmol) and5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 333, 288 mg, 0.623 mmol) and was used without furtherpurification. Yield 500 mg 95%.

LCMS Rt=1.58 minutes, m/z 841 [M³⁵ClH]+

TLC Rf=0.6 (ethyl acetate:heptane 1:1)

Preparation 6822-{1-[1-(Diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}-4-fluorophenol

1-(diphenylmethyl)-3-hydrazinoazetidine dihydrochloride (Preparation690, 1.25 g, 4.30 mmol) was stirred in ethanol (20 ml) and acetic acid(8 ml) for 30 minutes with ice cooling to give a suspension. To thiscold suspension was added(2E)-3-(dimethylamino)-1-(5-fluoro-2-hydroxyphenyl)prop-2-en-1-one(Preparation 221, 900 mg, 4.3 mmol), stirred at 0° C. for 1 hour thenallowed to warm up to room temperature over 18 hours. The reactionmixture was evaporated and then partitioned between ethyl acetate (100ml), water (50 ml) and saturated aqueous sodium hydrogencarbonatesolution (30 ml). The organic layer was separated and back-washed withsaturated aqueous sodium chloride solution (2×20 ml), dried over sodiumsulphate, filtered and evaporated. The solid was triturated with diethylether and the off-white solid filtered. The solid was crystallized fromethyl acetate:hexane (1:4) to give the title compound as colourlesscrystals were. Yield 490 mg 29%.

LCMS Rt=1.36 minutes m/z 400 [MH]+

¹HNMR (CDCl₃): δ 3.61 (m, 4H), 4.60 (s, 1H), 4.88 (m, 1H), 5.2 (brs,1H), 6.80 (m, 1H) 6.89 (m, 1H), 7.03 (m, 1H), 7.16 (m, 2H), 7.26 (m,4H), 7.42 (m, 4H), 7.71 (s, 1H).

TLC Rf=0.6 (ethyl acetate:heptane 1:1)

Preparation 683 tert-Butyl{[5-chloro-4-(2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}-4-fluorophenoxy)-2-fluorophenyl]sulfonyl}1,3-thiazol-4-ylcarbamate

Prepared by analogy to Preparation 680 from2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}-4-fluorophenol(Preparation 682, 97.1 mg, 0.243 mmol) and tert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate(Preparation 453, 100 mg, 0.243 mmol). Yield 145 mg 76%.

LCMS Rt=1.58 minutes, m/z 790 [M³⁵ClH]+

¹HNMR (CD₃OD): δ 1.31 (s, 9H), 3.55 (m, 4H), 4.60 (s, 1H), 4.97 (m, 1H),6.31 (s, 1H), 6.58 (d, 1H), 7.17 (m, 2H), 7.26 (m, 5H), 7.39 (m, 6H),7.51 (d, 1H), 7.55 (d, 1H), 8.00 (d, 1H), 8.87 (d, 1H).

TLC Rf=0.7 (ethyl acetate:heptane 1:1)

Preparation 6884-(4-chloro-2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}phenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 647, 157 mg, 0.353 mmol),4-chloro-2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}phenol(Preparation 689, 147 mg, 0.353 mmol) and potassium carbonate (147 mg,1.06 mmol) were stirred in dimethyl sulphoxide (1.0 ml) for 18 hours.The mixture was partitioned between methyl-t-butyl ether (40 ml) andwater (20 ml), the organic layer was dried over anhydrous sodiumsulphate, filtered and evaporated to give the title compound as a glass,270 mg.

LCMS Rt=1.60 minutes, m/z=841 [M³⁵ClH]+

¹HNMR (CDCl₃): δ 3.56-3.66 (m, 7H), 3.70 (s, 3H), 4.61 (s, 1H),4.79-4.88 (m 1H), 5.27 (s, 2H), 6.14-6.19 (m, 1H), 6.25-6.35 (m, 2H),7.00 (d, 1H), 7.13-7.21 (m, 3H), 7.24-7.35 (m, 6H), 7.40-7.50 (m, 6H),7.54 (s, 1H), 8.18 (s, 1H).

Preparation 6894-chloro-2-{1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazol-5-yl}phenol

1-(diphenylmethyl)-3-hydrazinoazetidine dihydrochloride (Preparation690, 1.00 g, 3.06 mmol) was added to an ice cold, stirred suspension of(2E)-1-(5-chloro-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one(Preparation 759, 700 mg, 3.1 mmol) in ethanol (5 ml) and acetic acid (5ml), stirred at 0° C. for 2 hours then allowed to warm up to roomtemperature over 2 hours. The solvents were removed in vacuo and theresidue partitioned between ethyl acetate (80 ml) and saturated aqueoussodium hydrogencarbonate solution (50 ml). The organic layer wasseparated and dried over sodium sulphate, filtered and the solventsremoved in vacuo to give a yellow gum. This was dissolved in warmmethyl-t-butyl ether (20 ml) and allowed to crystallize to give thetitle compound as a pale yellow powder, 541 mg, yield 42%.

LCMS Rt=1.30 minutes, m/z 416 [M³⁵ClH]⁺

¹HNMR (CDCl₃): δ 3.59-3.67 (m, 4H), 4.61 (s, 1H), 4.81-4.91 (m, 1H),6.33 (s, 1H), 6.90 (d, 1H) 7.08 (d, 1H), 7.16-7.22 (m, 2H), 7.23-7.31(m, 5H), 7.40-7.45 (m, 4H), 7.70 (m, 1H).

The title compound can also be made using the following method:

1-(diphenylmethyl)azetidin-3-yl methanesulfonate (0.1 g, 0.000315 mol)was suspended in hydrazine hydrate (0.61 mL, 0.0126 mol) and thereaction heated to 70° C. for 6 hours under nitrogen. The reaction wascooled, solvent was removed in vacuo then left under vacuum to dry for18 hours. The resulting solid was suspended in ethanol (10 mL) andacetic acid (3 mL),(2E)-1-(5-chloro-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one(Preparation 759, 0.09 g, 0.0004 mol) was added and the reaction stirredat room temperature for 2 hours. Solvent removed in vacuo and crudepurified by ISCO® (using 0-30% ethyl acetate in heptane, 12 g SiO₂) torecover the title compound as a pale yellow solid, 43 mg, yield=33%.

LCMS Rt=1.29 minutes, MS m/z 416 [M³⁵ClH]+

¹HNMR (CDCl₃): δ 3.64 (m, 4H), 4.66 (s, 1H), 4.89 (m, 1H), 6.33 (s, 1H),6.90 (d, 1H) 7.08 (d, 1H), 7.19 (m, 2H), 7.28 (m, 5H), 7.42 (m, 4H),7.70 (m, 1H).

Preparation 690 1-(diphenylmethyl)-3-hydrazinoazetidine dihydrochloride

To a stirred suspension of tert-butyl2-[1-(diphenylmethyl)azetidin-3-yl]hydrazinecarboxylate (Preparation691, 19.3 g, 54.6 mmol) in 1,4-dioxane (64 ml) was added 4M hydrogenchloride in 1,4-dioxane (290 ml) at 0° C. and stirred at roomtemperature for 4 hours. Then the reaction mixture was concentrated invacuo and the residue was triturated with diethyl ether to give 15 g(85%) of the title compound as a white solid.

TLC Rf=0.2 (dichloromethane:methanol, 95:5)

¹HNMR (d₆-DMSO): δ 3.90-4.20 (m, 5H), 5.90-6.06 (m, 1H), 7.36-7.45 (m6H), 7.60-7.76 (m 4H), 9.55 (br, 3H), 12.70 (br, 1H).

Preparation 691 tert-butyl2-[1-(diphenylmethyl)azetidin-3-yl]hydrazinecarboxylate

To a stirred solution of tert-butyl2-[1-(diphenylmethyl)azetidin-3-ylidene]hydrazinecarboxylate(Preparation 692, 15.8 g, 45 mmol) in acetic acid (126 ml) was addedsodium cyanoborohydride (2.82 g, 45 mmol) portionwise at roomtemperature and stirred at room temperature for 4 hours. Then thereaction mixture was concentrated in vacuo. The pH was adjusted to 8-10with 1M aqueous sodium hydroxide solution and extracted withdichloromethane (3×200 ml). The combined organic layer was washed withwater (3×150 ml), saturated aqueous sodium chloride solution (150 ml),dried over anhydrous sodium sulphate and concentrated in vacuo. Thecrude product was triturated with diethyl ether to get 15 g (94%) of thetitle compound as a white solid.

TLC Rf=0.3 (ethyl acetate:hexane, 1:1)

¹HNMR (CDCl₃): δ 1.43 (s, 9H), 3.27 (brs, 2H), 3.68 (brs, 2H), 3.90(brs, 1H), 4.67 (brs, 1H), 6.21 (brs, 1H), 7.21-7.25 (m, 2H), 7.28-7.32(m, 4H), 7.43-745 (m, 4H).

Preparation 692 tert-butyl2-[1-(diphenylmethyl)azetidin-3-ylidene]hydrazinecarboxylate

To a stirred solution of 1-(diphenylmethyl)azetidin-3-one (Preparation693, 11.4 g, 48 mmol) and tert-butyl hydrazinecarboxylate (6.3 g, 48mmol) in methanol (110 ml) at 0° C. was added acetic acid (5.56 ml, 96mmol) dropwise and stirred at room temperature for 18 hours. Then thereaction mixture was concentrated in vacuo and the residue was dissolvedin dichloromethane (500 ml). The organic layer was washed with 1Maqueous sodium hydroxide solution (2×150 ml), water (3×150 ml),saturated aqueous sodium chloride solution (150 ml), dried overanhydrous sodium sulphate and concentrated in vacuo. The crude productwas triturated with diethyl ether to get 15.8 g (94%) of the titlecompound as a white solid.

TLC Rf=0.25 (ethyl acetate:hexane, 1:4)

¹HNMR (CDCl₃): δ 1.45 (s, 9H), 3.85 (s, 2H), 3.97 (s, 2H), 4.51 (s, 1H),7.12-7.21 (m, 2H), 7.25-7.29 (m, 4H), 7.40-7.42 (m, 4H).

Preparation 693 1-(diphenylmethyl)azetidin-3-one

To a stirred solution of 1-(diphenylmethyl)azetidin-3-ol hydrochloridesalt, (20 g, 72.5 mmol) in tetrahydrofuran (69 ml) and DMSO (173 ml) wasadded triethylamine (50.5 ml, 362.6 mmol) at 0° C. Then sulphurtrioxide:pyridine complex (69 g, 433 mmol) was added portionwise to thereaction mixture over 10 minutes. The resulting yellow solution wasstirred at room temperature for 2 hours. Then the reaction mixture waspoured in to cold water (173 ml) and extracted with (1:1) ethylacetate:hexane (5×200 ml). The combined organic layer was washed withwater (200 ml), saturated aqueous sodium chloride solution (200 ml),dried over anhydrous sodium sulphate and concentrated in vacuo. Crudeproduct was purified over 100-200 silica gel using 5% v/v ethyl acetatein hexane to get 11.4 g (67%) of the title compound as a white solid.

TLC Rf=0.8 (ethyl acetate:hexane, 3:7)

¹HNMR (CDCl₃): δ 3.99 (s, 4H), 4.58 (s, 1H), 7.19-7.22 (m, 2H),7.27-7.31 (m, 4H), 7.46-7.48 (m, 4H).

Preparation 696 tert-butyl 3-hydrazinoazetidine-1-carboxylate

tert-butyl 3-iodoazetidine-1-carboxylate (2 g, 0.007 mol) and hydrazinehydrate (3.44 mL, 0.07 mol) were combined and the reaction heated to 80°C. for 18 hours under nitrogen. The reaction was cooled and reactionpartitioned between ethyl acetate (30 mL) and water (30 mL). The aqueouslayer was extracted a further 3 times with dichloromethane (3×30 mL).The organic extracts were combined and solvent removed in vacuo to givea clear oil (0.87 g) which was a 2:1 mix of title product todi-tert-butyl 3,3′-hydrazine-1,2-diyldiazetidine-1-carboxylate

LCMS Rt=0.28 minutes MS m/z no mass ion detected

¹HNMR (CDCl₃) δ 1.42 (s, 9H), 2.36 (m, 3H), 4.01 (m, 2H).

Preparation 7113-cyano-N-(2,4-dimethoxybenzyl)-4-[2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

To a solution of 2-pyridazin-4-yl-4-(trifluoromethyl)phenol (Preparation712, 60.6 mg, 0.25 mmol) in dimethylsulfoxide (2.5 mL) was added3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 68, 109.2 mg, 0.25 mmol) followed by potassium carbonate(101.7 mg, 0.74 mmol). The resulting mixture was stirred overnight atroom temperature under nitrogen. The reaction mixture was poured intowater (125 mL), and extracted with ethyl acetate (3×25 mL). The combinedorganic extract was washed successively with aqueous sodium hydroxidesolution (1M, 15 mL) and saturated aqueous sodium chloride solution(4×25 mL), dried over anhydrous sodium sulfate, filtered and the solventremoved in vacuo. The resulting residue was purified by columnchromatography using a gradient of 25-40% v/v ethyl acetate in heptaneto give the title compound as a white foam (59.7 mg, 36%).

LCMS Rt=3.47 minutes, MS m/z 655 [MH]+

¹HNMR (CDCl₃): δ 3.56 (s, 3H), 3.80 (s, 3H), 5.33 (s, 2H), 6.17 (m, 1H),6.34-6.37 (m, 1H), 6.73-6.76 (m, 1H), 7.10 (m, 1H), 7.20 (m, 1H), 7.76(m, 2H), 7.81-7.86 (m, 3H), 8.22 (s, 1H), 9.34 (m, 1H), 9.38 (m, 1H).

Method 2

An alternative method of preparing Preparation 711 is as follows.

A mixture of3-Cyano-N-(2,4-dimethoxybenzyl)-4-[2-iodo-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 429, 33.07 g, 47.08 mmol) in dimethylformamide (140 mL) wastreated with copper (I) iodide (1830 mg, 9.60 mmol) and cesium fluoride(14.4 g, 94.2 mmol). The mixture was sparged with nitrogen for 15minutes. Then 4-(tributylstannyl)pyridazine (19.1 g, 51.8 mmol)dissolved in dimethylformamide (10 mL) was added and the reaction heatedto 30° C. The reaction was cooled, poured onto water (1 L) and extractedwith diethylether (4×450 mL). The combined extracts were washed withwater (6×500 mL), dried over magnesium sulfate and evaporated to furnishan orange foam. This residue was purified using column chromatography(using a gradient of 100% heptane with 2% triethylamine to 40:60ethylacetate:heptane with 2% triethylamine) to furnish the titlecompound as an off-white solid.

Preparation 712 2-pyridazin-4-yl-4-(trifluoromethyl)phenol

Method 1

To a solution of 2-iodo-4-trifluoromethylphenol (360. mg, 1.25 mmol),4-(tributylstannyl)pyridazine (485.2 mg, 1.31 mmol) and cesium fluoride(376.5 mg, 2.47 mmol) in N,N-dimethylformide (2.90 mL) was added thetetrakis(triphenylphosphine)palladium(0) (70.9 mg, 0.061 mmol) andcopper(I) iodide (25.2 mg, 0.13 mmol). The resulting mixture wasevacuated and refilled with nitrogen five times and stirred at 45° C.for 21 hours under nitrogen. The reaction was concentrated in vacuo andthe residue partitioned between ethyl acetate (20 mL) and water (20 mL).The aqueous layer was extracted with ethyl acetate (3×20 mL) and thecombined organic extracts were washed with water (3×20 mL) and saturatedaqueous sodium chloride solution (20 mL). The organics were dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresulting residue was purified by column chromatography using a gradientof 25-60% v/v ethyl acetate in dichloromethane to give the titlecompound as a yellow-orange solid (150.3 mg, 50%).

LCMS Rt=2.42 minutes, MS m/z 241 [MH]+

¹HNMR (CDCl₃): δ 7.33 (m, 1H), 7.64 (m, 1H), 7.68 (m, 1H), 7.79 (m, 1H),9.31 (m, 1H), 9.74 (m, 1H).

Method 2

An alternative method of preparing Preparation 712 is as follows.

To a suspension of 4-(5-trifluoro-2-methoxyphenyl)pyridazine(Preparation 896, 0.045 g, 0.00177 mol) in dichloromethane (5.0 mL) at0° C. under nitrogen was added tribromoborane in dichloromethane (1.0 Msolution, 0.53 mL, 0.00053 mol). This was stirred at room temperatureunder nitrogen for 18 hours. The reaction was diluted in water (10.0 mL)and stirred at room temperature for 10 minutes before adding a solutionof aqueous saturated ammonium chloride (10.0 mL) and a 2M (aq) HClsolution (10.0 mL). Dichloromethane was added (10.0 mL) and the organiclayer was discarded. The aqueous layer was brought to neutral pH addinga saturated aqueous solution of sodium hydrogen carbonate followed byextraction with dichloromethane (15 mL). The organic layer was driedover sodium sulphate, filtered, and concentrated in vacuo. The residuewas triturated in dichloromethane (5.0 mL) and the title compound wasisolated as a pale yellow solid.

LCMS Rt=1.44 minutes MS m/z 241 [MH]+

¹H NMR (400 MHz, d₆-DMSO): δ 7.20 (d, 1H), 7.65 (d-d, 1H), 7.80 (s, 1H),7.90 (m, 1H), 9.25 (d, 1H), 9.50 (s, 1H), 11.10 (s, 1H)

Method 3

A further alternative method of preparing Preparation 712 is as follows.

To a 5 L jacketed vessel was added acetonitrile (9 L) and the solventwas sparged with nitrogen for 2 hours. To the solvent was added cesiumfluoride (335.8 g, 2.21 moles), 4-(tributylstannyl)pyridazine (408 g,1.11 moles), 4-trifluoromethyl-6-iodophenol (318.33 g, 1.11 moles),palladium tetrakis triphenylphosphine (61.31 g, 53.05 mmole) and copper(I) iodide (40 g, 210 mmol) at 20° C. The resulting orange suspensionwas heated to 45-50° C. for 2 hours. The reaction was cooled andpartitioned between tert-butylmethylether (2×5 L) and 2N (aq) HCl (2×5L). The resulting biphasic solution was filtered and the layersseparated. The aqueous phases were combined and basified with 4M (aq)sodium hydroxide solution (6 L) to obtain a pH=4-5. The resultingsuspension was extracted into ethyl acetate (10 L) and the organic layerconcentrated to dryness to afford an orange solid as the title compound(60%).

Method 4

Yet another alternative method for the preparation of Preparation 712 isas follows.

2-(3-furyl)-4-(trifluoromethyl)phenyl acetate (Preparation 899, 0.44 g,0.0018 mol) was dissolved in dichloromethane (10 mL) then zinc triflate(0.03 g, 0.00008 mol) added. The reaction was heated to 40 degreescelcius and di-tert butyl azodicarboxylate (0.45 g, 0.002 mol) addedportionwise over 2 hours. The reaction was then stirred at 45 degreescelcius for 72 hours. Acetic acid (0.5 mL) was then added and thereaction stirred at 45 degrees celcius for 48 hours. The reaction wascooled to room temperature and 2M aqueous sodium hydroxide (30 mL)added. The resultant solution was stirred vigorously for 30 minutes. Theaqueous layer was then separated, acidified to pH=1 with concentratedaqueous hydrogen chloride and washed with dichloromethane (10 mL). Thereaction was brought to pH=6 with sodium bicarbonate and extracted withethyl acetate (2×50 ml). The organics were combined and concentrated invacuo to give the title compound as a brown solid (0.29 g, 64% yield)LCMS Rt=1.46 min; MS m/z 241 [MH]+

1H NMR (400 MHz, d₆-DMSO): δ 7.17 (d 1H) 7.66 (dd 1H) 7.81 (d 1H), 7.92(dd 1H), 9.25 (dd, 1H), 9.49 (m 1H) 11.09 (s 1H)

Preparation 7163-chloro-4-fluoro-N-(methoxymethyl)-N-pyrimidin-4-ylbenzenesulfonamideand3-chloro-4-fluoro-N-[(4E)-3-(methoxymethyl)pyrimidin-4(3H)-ylidene]benzenesulfonamideand3-chloro-4-fluoro-N-[(4E)-1-(methoxymethyl)pyrimidin-4(1H)-ylidene]benzenesulfonamide

To 3-chloro-4-fluoro-N-pyrimidin-4-ylbenzenesulfonamide (Preparation426, 73 mg, 0.25 mmol) in methylene chloride (2 mL) cooled at 0° C. wasadded N,N-diisopropylethylamine (0.066 mL, 0.38 mmol) and chloromethylmethyl ether (0.025 mL, 0.28 mmol). After stirring at room temperaturefor 18 hours, the reaction mixture was diluted with ethyl acetate,washed successively with 1N aqueous sodium hydroxide, water, saturatedaqueous sodium chloride solution, dried over anhydrous sodium sulfateand concentrated to give 76 mg (90%) of the title compound as an orangeoil and a mixture of three regioisomers that were not separated.

LCMS Rt=1.64 (major), 1.33 & 1.46 minutes, MS m/z 332 [MH]+.

Preparation 7195-chloro-N-(ethoxymethyl)-2,4-difluoro-N-pyrimidin-4-ylbenzenesulfonamideand5-chloro-N-[(4E)-1-(ethoxymethyl)pyrimidin-4(1H)-ylidene]-2,4-difluorobenzenesulfonamideand5-chloro-N-[(4E)-1-(ethoxymethyl)pyrimidin-4(1H)-ylidene]-2,4-difluorobenzenesulfonamide

Prepared according to the process of Preparation 716 using5-chloro-2,4-difluoro-N-pyrimidin-4-ylbenzenesulfonamide, Preparation723 and chloromethyl ethyl ether. The product was a mixture of threeregioisomers that were not separated and used in subsequent reactions asa mixture.

LCMS Rt=1.71 (major), 1.41 & 1.55 (minor) minutes, MS m/z 364 [MH]+.

Preparation 721 2-(2-aminopyridin-4-yl)-4-chlorophenol

5-chloro-2-hydroxyphenylboronic acid (200 mg, 1 mmol),2-amino-4-bromopyridine (220 mg, 1.3 mmol), sodium carbonate (490 mg,4.6 mmol), and tetrakis(triphenylphosphine)palladium (0) (130 mg, 0.12mmol) were all placed in a round bottom flask and 1,4-dioxane (3 mL) andwater (1 mL) were added. The mixture was heated to 85° C. for 2 hours.The mixture was cooled to room temperature and diluted with ethylacetate and water. The layers were separated and the aqueous layer wasextracted with ethyl acetate (1×). The combined extracts were dried overanhydrous magnesium sulfate and concentrated in vacuo. The residue waspurified by column chromatography (12 g silica gel column, 0-100% v/vethyl acetate/hexanes gradient elution) to afford the title compound(242 mg).

LCMS Rt=1.05 minutes, MS m/z 221 [MH]+

¹HNMR (d₆-DMSO): δ 5.87 (m, 2H), 6.63 (m, 2H), 6.93 (m, 1H), 7.22 (m,2H), 7.90 (d, 1H), 9.98 (bs, 1H).

Preparation 723 5-chloro-2,4-difluoro-N-pyrimidin-4-ylbenzenesulfonamide

A mixture of 4-aminopyrimidine (1.30 g, 13.7 mmol) and1,4-diazabicyclo[2.2.2]octane (1.54 g, 13.7 mmol) were addedconcurrently to a solution of 5-chloro-2,4-difluorobenzenesulfonylchloride (3.4 g, 14 mmol) in anhydrous acetonitrile (63 mL). Thereaction mixture immediately turned yellow and a precipitate formed. Thereaction mixture was stirred under argon. After 72 hours, the reactionmixture was filtered and the filtrate was concentrated in vacuo to givea residue. The residue was partitioned between 1M hydrochloric acid andethyl acetate. The organic phase was separated, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The residue was partiallypurified by automated flash column chromatography using an 80 g silicagel ISCO™ column using hexanes to 1% v/v acetic acid in ethyl acetategradient elution. The product was purified a second time by reversephase HPLC to give the title compound (193 mg, 5%) as a white solid.

LCMS Rt=1.22 minutes, MS m/z 307 [M³⁷ClH]+, 305 [M³⁵ClH]+

¹HNMR (d₆-DMSO): δ 6.93 (m, 1H), 7.72 (m, 1H), 8.04 (m, 1H), 8.20 (m,1H), 8.56 (s, 1H), 13.53 (br s, 1H).

Preparation 728 tert-butyl4-[5-chloro-2-(2-cyano-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}phenoxy)-4-fluorophenyl]-1H-pyrazole-1-carboxylate

The title compound was prepared using a method analogous to that forPreparation 733 below, using3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 68) and tert-butyl4-(5-chloro-4-fluoro-2-hydroxyphenyl)-1H-pyrazole-1-carboxylate(Preparation 743). Purification was by column chromatography (silica,heptane-ethyl acetate 10-60% v/v).

LCMS Rt=4.39 minutes MS m/z=728 [M³⁵ClH]+

¹HNMR (d₆-DMSO): δ 1.55 (s, 9H), 3.6 (s, 3H), 3.75 (s, 3H), 5.20 (s,2H), 6.4 (m, 2H), 6.95-7.10 (m, 2H), 7.70 (m, 2H), 7.95 (m, 1H), 8.2 (s,1H), 8.30 (d, 1H), 8.40 (m, 1H), 8.55 (s, 1H).

Preparation 7334-(5-chloro-4-fluoro-2-iodophenoxy)-3-cyano-N-(2,4-dimethoxybenzyl)-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

To a solution of3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide(Preparation 68, 335 mg, 0.77 mmol) in dimethylsulfoxide (10 ml), wasadded 5-chloro-4-fluoro-2-iodophenol (Preparation 734, 200 mg, 0.73mmol) and potassium carbonate (229 mg, 1.47 mmol). The flask was purgedwith nitrogen (3×). The resulting suspension was allowed to stir at roomtemperature for 18 hours. The reaction was poured into a 1M aqueoussolution of sodium hydroxide, and extracted with dichloromethane (3×).The combined organic phase was then dried over anhydrous magnesiumsulfate, filtered and the solvent removed in vacuo to leave the desiredproduct as an off white solid (504 mg, 100%).

LCMS Rt=4.70 minutes, no mass ion observed.

¹HNMR (CDCl₃): δ 3.62 (s, 3H), 3.80 (s, 3H), 5.35 (s, 2H), 6.26 (s, 1H),6.34-6.38 (m, 1H), 6.49-6.55 (m, 1H), 7.04-7.09 (m, 1H), 7.18-7.22 (m,1H), 7.67-7.71 (m, 1H), 7.77-7.83 (m, 2H), 8.22 (s, 1H).

Preparation 734 5-chloro-4-fluoro-2-iodophenol

N-iodosuccinimide (4.61 g, 20.5 mmol), was suspended in glacial aceticacid (20 ml). To this suspension was added 3-chloro-4-fluorophenol (3.0g, 20.0 mmol) and then concentrated sulphuric acid (0.36 ml, 6.14 mmol)was added dropwise over 5 minutes. The resulting brown/orange suspensionwas stirred at room temperature for 18 hours. The mixture wasconcentrated in vacuo and the residue was partitioned between water anddichloromethane, the dichloromethane was dried over anhydrous magnesiumsulphate, filtered and concentrated in vacuo to give an orange/red oil.The crude product was purified by column chromatography on silica gelusing 1:1 ethyl acetate:heptane to give the title compound as a paleorange/brown solid (3.50 g, 60% yield)

LCMS Rt=2.83 minutes, m/z=271 [M³⁵ClH]−; 273 [M³⁷ClH]−

¹HNMR (CDCl₃): δ 5.33 (s, 1H), 7.02 (d, 1H), 7.43 (d, 1H)

Preparation 743 tert-butyl4-(5-chloro-4-fluoro-2-hydroxyphenyl)-1H-pyrazole-1-carboxylate

Prepared using the method of Example 587 using4-chloro-5-fluoro-2-iodophenol (Preparation 744, 386 mg, 1.42 mmol) andtert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(500 mg, 1.70 mmol) gave the title compound as a white solid (200 mg,38%).

LCMS Rt=3.43 minutes, MS m/z 312 [M³⁵ClH]+

¹HNMR (d₆-DMSO): δ 1.60 (s, 9H), 6.90 (m, 1H), 7.90 (m, 1H), 8.40 (s,1H), 8.60 (s, 1H).

Preparation 744 4-chloro-5-fluoro-2-iodophenol

To a suspension of N-iodosuccinamide (6.1 g, 27.3 mmol) in glacialacetic acid (23 mL) was added 4-chloro-3-fluorophenol (4.0 g, 27.3 mmol)and after 5 minutes sulphuric acid was added (0.5 mL, 8.2 mmol) and thereaction mixture was left to stir at room temperature for 16 hours. Thereaction was quenched by addition of water (30 mL) and the compound wasextracted into dichloromethane (3×30 mL). The combined organic layerswere washed with 10% sodium metabisulphite aqueous solution (2×20 mL),then saturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulphate, filtered and evaporated in vacuo. The crude materialwas purified by flash column chromatography (silica, toluene) to affordthe desired product as an oil (4.0 g, 54%).

LCMS=3.10 minutes, MS m/z=270 [M³⁵ClH]−

¹HNMR (d₆-DMSO): δ 6.80 (m, 1H), 7.85 (d, 1H), 11.1 (s, 1H).

Preparation 759(2E)-1-(5-chloro-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one

To a solution of 1-(5-chloro-2-hydroxyphenyl)ethanone (17.2 g, 100.8mmol) in propan-2-ol (100 ml) was added1,1-dimethoxy-N,N-dimethylmethanamine (27 ml, 200 mmol) dropwise and thereaction mixture was warmed to 45° C. and stirred for 24 hours. Theresulting suspension was cooled in ice, filtered and washed withpropan-2-ol then tert-butyl methyl ether. The solid was dried in vacuoto give the title compound as a bright yellow solid, 16.39 g, 72% yield.

LCMS Rt=1.48 minutes, MS m/z 226 [M³⁵ClH]+; 228 [M³⁷ClH]+

¹HNMR (d₆-DMSO): δ 3.00 (s, 3H), 3.19 (s, 3H), 6.00 (d, 1H), 6.79 (d,1H), 7.35 (m, 1H), 7.92 (d, 1H), 8.00 (s, 1H).

Preparation 7603-cyano-N-(1,2,4-thiadiazol-5-yl)-4-[2-iodo-4-(trifluoromethoxy)phenoxy]benzenesulfonamide

To a suspension of 2-iodo-4-(trifluoromethoxy)phenol (Preparation 226,600 mg, 1.97 mmol) and potassium carbonate (1125 mg, 8.14 mmol) inDimethylsulfoxide (10 mL) was added3-cyano-4-fluoro-N-[1,2,4]thiadiazol-5-yl-benzenesulfonamide(Preparation 65). The reaction was heated to 80° C. under N₂ for 7 hoursbefore the addition of ethyl acetate (20 mL) and 3M aqueous HCl solution(30 mL). The organic layer was collected, washed with brine (20 mL),dried over sodium sulphate and concentrated in vacuo. The residue wastriturated in dichloromethane and filtered to afford 965 mg of the titlecompound.

LCMS Rt=1.90 minutes. MS m/z 569 [MH]+

¹H NMR (d₆-DMSO): δ 6.90 (d, 1H), 7.55-7.760 (m, 2H), 8.00 (m, 2H), 8.35(s, 1H), 8.45 (s, 1H)

Preparation 850

Tert-butyl3-{5-[5-chloro-2-(4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}-2,5-difluorophenoxy)phenyl]-1H-pyrazol-1-yl}azetidine-1-carboxylate

Tert-butyl3-[5-(5-chloro-2-hydroxyphenyl)-1H-pyrazol-1-yl]azetidine-1-carboxylate(Preparation 851, 80.0 g, 0.2287 mol) and potassium carbonate (94.82 g,0.686 mol) were combined in dimethylsulphoxide (600 mL). To this slurrywas addedN-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide,(Preparation 647, 101.87 g, 0.2287 mol) and stirred at room temperaturefor 4.5 hours. Ethyl acetate (1600 mL) and water (1000 mL) were addedand the layers separated. The ethyl acetate was washed with water (2×800mL), then saturated aqueous sodium chloride solution (200 mL) and thendried over anhydrous magnesium sulphate. To this suspension,tert-butylmethyl ether (250 mL) was added and the mixture was washedwith dilute aqueous sodium chloride solution (1000 mL), the organicswere dried over magnesium sulphate, filtered and the solvents removedin-vacuo to give a pale yellow solid. This solid was dissolved indichloromethane (500 mL) and tert-butylmethyl ether was added graduallywhilst evaporating the dichloromethane in vacuo to give a whiteprecipitate which was filtered off and washed with a littletert-butylmethyl ether to give the title compound as a white solid,(145.47 g).

HPLC Rt=4.04 minutes

¹HNMR (CDCl₃) δ 1.47 (s, 9H), 3.65 (s, 3H), 3.78 (s, 3H), 4.30 (m, 2H),4.42 (m, 2H), 4.84-4.91 (m, 1H), 5.31 (s, 2H), 6.17 (d, 1H), 6.22 (d,1H), 6.26-6.31 (m, 1H), 6.35-6.37 (m, 1H), 7.02 (d, 1H), 7.19 (d, 1H),7.41 (d, 1H), 7.45-7.50 (m, 1H), 7.51-7.53 (m, 1H), 7.62 (d, 1H), 8.21(s, 1H).

Preparation 851

Tert-butyl3-[5-(5-chloro-2-hydroxyphenyl)-1H-pyrazol-1-yl]azetidine-1-carboxylate

Tert-butyl 3-hydrazinoazetidine-1-carboxylate, (Preparation 696, 88.37g, 0.4247 mol) was dissloved in ethanol (883.7 mL) and the solution wascooled to 0° C. in an ice bath. Acetic acid (97.36 mL, 1.70 mol) wasadded followed by(2E)-1-(5-chloro-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one,(Preparation 852, 95.86 g, 0.4247 mol) and the resulting slurry wasallowed to warm to room temperature then stirred at room temperature for2 days. The resulting suspension was cooled to 0° C. and the solid wasfiltered off, washed with cold ethanol (2×40 mL) and dried to give thetitle compound as a white granular solid, (83.23 g).

HPLC Rt=3.12 minutes

¹HNMR (d₆-DMSO): δ 1.39 (s, 9H), 4.10-4.24 (m, 4H), 4.80-4.89 (m, 1H),6.29 (s, 1H), 6.97 (d, 1H), 7.20 (s, 1H), 7.33 (dd, 1H), 7.63 (s, 1H).

Preparation 852(2E)-1-(5-Chloro-2-hydroxyphenyl)-3-(dimethylamino)prop-2-en-1-one

1-(5-chloro-2-hydroxyphenyl)ethanone, (165 g, 0.967 mol) was slurried in2-propanol (1000 mL) then 1,1-dimethoxy-N,N-dimethylmethanamine (258.28mL, 1.93 mol) was added and the resulting yellow solution was stirred at45° C. for 18 hours. The resulting suspension was cooled to roomtemperature and stirred for a further 48 hours. The solid was filteredoff, washed with 2-propanol (2×200 mL) and then tert-butylmethyl ether(200 mL) then dried to give the title compound as a bright yellow solid,(204.59 g).

HPLC Rt=5.25 minutes

¹HNMR (CDCl₃) δ 2.99 (s, 3H), 3.21 (s, 3H), 5.67 (d, 1H), 6.88 (d, 1H),7.29 (dd, 1H), 7.63 (d, 1H), 7.89 (d, 1H), 13.97 (s, 1H).

Preparation 853 tert-Butyl4-(4-(5-chloro-2-hydroxyphenyl)pyridin-2-yl)piperazine-1-carboxylate

A mixture of 4-chloro-2-iodophenol (367 mg, 1.44 mmol), tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate(707.5 mg, 1.817 mmol), and sodium carbonate (615.0 mg, 5.802 mmol) in1,4-dioxane (6.0 mL, 77 mmol) and water (2.0 mL, 110 mmol) was sparged 5minutes with argon. Tetrakis(triphenylphosphine)palladium(0) (100.0 mg,0.08654 mmol) was added, the vial was capped, and the reaction mixturewas heated at 90° C. After 4 hours, the reaction mixture was cooled toambient temperature and poured into water. Saturated aqueous ammoniumchloride was added, and the mixture was extracted with ethyl acetate(3×). The combined organic layers were washed with brine, dried oversodium sulfate, filtered, and concentrated onto diatomaceous earth. Theresidue was purified by automated flash chromatography (24 g SiO₂,hexanes to ethyl acetate) to afford the product as an amber oil thatsolidified on standing (491 mg, 74%).

LC/MS Rt=1.66 minutes, MS m/z 390 [M³⁵ClH]+

¹H NMR (d₆-DMSO): δ 10.01 (s, 1H), 8.12 (d, 1H), 7.35 (d, 1H), 7.25 (m,1H), 6.94 (m, 2H), 6.88 (m, 1H), 3.51 (m, 4H), 3.43 (m, 4H), 1.42 (s,9H).

Preparation 854 tert-Butyl[(2,4,5-trifluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate

The above titled compound was prepared from2,4,5-trifluorobenzenesulfonyl chloride (5.0 g, 0.022 mol) andthiazole-4-yl-carbamic acid tert-butyl ester (Preparation 72, 4.3 g,0.022 mol) using the method of Preparation 453 to afford the product asa white solid (6.84 g, 80%).

LC/MS Rt=1.65 minutes, MS m/z 395 [MH]+

¹H NMR (d₆-DMSO): δ 9.14 (d, 1H), 8.19 (m, 1H), 8.03 (m, 2H), 1.28 (s,9H).

Preparation 8552-[1-(1-Methylazetidin-3-yl)-1H-pyrazol-5-yl]-4-(trifluoromethyl)phenol

2-(1-Azetidin-3-yl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenol,(Preparation 856, 190 mg, 0.00067 mol) was stirred in dichloromethane (5mL), methanol (0.5 mL) and acetic acid (0.1 mL). Aqueous formaldehyde(0.25 mL of 37% wt/vol, 0.00336 mol) was added and the reaction stirredat room temperature for 15 minutes. Sodium triacetoxyborohydride (711mg, 0.00336 mol) was added and the reaction stirred at room temperaturefor 4 hours. The solvents were removed in vacuo and the residuedissolved in water. Aqueous ammonium hydroxide (7.5 molar) was added topH 10 to give a white precipitate. The mixture was extracted with ethylacetate (1×20 mL). The organic layer was separated and washed withsaturated aqueous sodium chloride solution (2×10 mL). The organic layerwas separated, dried over anhydrous sodium sulphate, filtered and thesolvents removed in vacuo to give the title compound as a foam. (140mg).

LCMS Rt=0.97 minutes, MS m/z=298 [MH]+

TLC dichloromethane:methanol:acetic acid 95:5:0.5, Rf=0.4

¹HNMR (CDCl₃) δ 2.64 (s, 3H) 3.92-4.04 (m, 4H) 5.05-5.12 (m, 1H) 6.28(s, 1H) 6.76 (d, 1H) 7.49-7.52 (m, 2H) 7.68 (s, 1H).

Preparation 8562-(1-Azetidin-3-yl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenol

Trifluoroacetic acid (4 mL) was added to a stirred solution oftert-butyl3-{5-[2-hydroxy-5-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}azetidine-1-carboxylate,(Preparation 857, 375 mg, 0.001 mol) in dichloromethane (10 mL) undernitrogen and the solution was stirred for 3 hours. The pink solution wasevaporated and the residue dissolved in methanol and then the solventswere removed in vacuo. This was repeated a further two times. Theresidue was then suspended in diethyl ether and the solvents removed invacuo to give an off-white foam. The foam was dissolved in water andtreated with aqueous ammonia solution (7.5 molar) until pH10 to give awhite precipitate. The mixture was extracted with ethyl acetate (6×30mL). The combined organic layers were washed with saturated aqueoussodium chloride solution (2×20 mL), dried over anhydrous sodiumsulphate, filtered and the solvents removed in vacuo to give a solid.The solid was triturated with diethyl ether to give the title compoundas a white solid (200 mg).

LCMS Rt=0.97 minutes, MS m/z=284 [MH]+

TLC dichloromethane:methanol:formic acid 100:10:0.1, Rf=0.3.

¹HNMR (d₆-DMSO) δ 3.62-3.66 (m, 2H) 4.01-4.05 (m, 2H) 4.87-4.94 (m, 1H)6.29 (s, 1H) 7.05 (d, 1H) 7.40 (s, 1H) 7.57-7.60 (m, 2H).

Preparation 857 tert-Butyl3-{5-[2-hydroxy-5-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}azetidine-1-carboxylate

To a stirred solution of crude tert-butyl3-hydrazinoazetidine-1-carboxylate, (Preparation 858, 5.7 g, 0.030 mol)in ethanol (66 mL) at 0° C. was added acetic acid (6.6 mL) dropwise.Then(2E)-3-(dimethylamino)-1-[2-hydroxy-5-(trifluoromethyl)phenyl]prop-2-en-1-one,(Preparation 859, 6.4 g, 24.68 m mol) was added portionwise and allowedto stir at room temperature for 20 hours. The reaction mixture wasconcentrated in vacuo and neutralised with aqueous sodiumhydrogencarbonate solution. The mixture was extracted with ethyl acetate(150 mL). The combined organic layer was washed with water (100 mL),saturated aqueous sodium chloride solution (50 mL) and dried overanhydrous sodium sulphate. After concentration of organic layer invacuo, the crude product was washed with 20% v/v ethyl acetate in hexaneto get the title compound as a white solid (7.4 g).

LCMS Rt=3.52 minutes, MS m/z=384 [MH]+

¹HNMR (CDCl₃) δ 1.45 (s, 9H), 4.27-4.37 (m, 3H), 4.70 (brs, 1H),4.79-4.83 (m, 1H), 6.25 (s, 1H), 7.16 (d, 1H), 7.46 (s, 1H), 7.55 (d,1H), 7.66 (s, 1H), 9.64 (s, 1H).

HPLC Purity: 99.84%

Preparation 858

Tert-butyl 3-hydrazinoazetidine-1-carboxylate

Tert-butyl 3-iodoazetidine-1-carboxylate (142 g, 0.5016 mol) andhydrazine hydrate (245.21 mL, 5.02 mol) were mixed in ethanol (284 mL)and the reaction was heated to 85° C. for 48 hours under nitrogen. Thereaction was cooled and the ethanol was removed in vacuo. The residuewas partitioned between water (200 mL) and dichloromethane (300 mL), thewater layer was re-extracted with dichloromethane (2×200 mL), thecombined organics were dried over anhydrous magnesium sulphate, filteredand concentrated in vacuo to give the title compound as a colourlessoil, (88.37 g). This compound was used immediately in the next step.

¹HNMR (CDCl₃) δ 1.44 (s, 9H), 3.05 (br s, 3H) 3.65-3.76 (m, 3H),4.00-4.07 (m, 2H).

Preparation 859(2E)-3-(Dimethylamino)-1-[2-hydroxy-5-(trifluoromethyl)phenyl]prop-2-en-1-one

1-[2-Hydroxy-5-(trifluoromethyl)phenyl]ethanone, (Preparation 860, 7.0g, 0.0343 mol) was taken in dimethylformamide dimethylacetal (18.2 mL,0.137 mol) at room temperature and then heated at 110° C. for 30 min.The reaction mixture was concentrated in vacuo and the crude product wascrystallised from 2-propanol to give the title compound as bright yellowsolid (6.4 g).

LCMS Rt=1.61 minutes, MS m/z=260 [MH]+

¹HNMR (CDCl₃) δ 3.02 (s, 3H) 3.22 (s, 3H), 5.72 (d, 1H), 6.99 (d, 1H),7.55 (d 1H), 7.89-7.94 (m, 2H), 14.45 (s, 1H).

Preparation 860 1-[2-Hydroxy-5-(trifluoromethyl)phenyl]ethanone

To a stirred solution of 1-[2-methoxy-5-(trifluoromethyl)phenyl]ethanone(35 g, 0.160 mol) in dry dichloromethane (400 mL) at 0° C. was addedsolid tetrabutylammonium iodide (2.96 g, 0.008 mol) followed by borontribromide (33.96 mL, 0.353 mol) dropwise. After addition, the reactionmixture was stirred at room temperature for 90 minutes. The reactionmixture was cooled to 0° C. and quenched with ice. The mixture wasextracted with diethyl ether (1000 mL). The organic layer was washedwith water (2000 mL) and then saturated aqueous sodium chloride (1000mL). After concentration of the organic layer at room temperature invacuo, the crude product was purified by column chromatography (100-200silica gel, 2% v/v diethyl ether in hexane) to give 11.5 g (35%) of thetitle compound as a colourless oil.

GCMS Rt=5.59 minutes, MS m/z=204 [MH]+

¹HNMR (CDCl₃) δ 2.68 (s, 3H) 7.07 (d, 1H), 7.69 (d, 1H), 7.98 (s, 1H),12.53 (s, 1H).

Preparation 8614-{4-Chloro-2-[2-(cyclobutyloxy)pyridin-4-yl]phenoxy}-3-cyano-N-(2,4-dimethoxybenzyl)-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

4-Chloro-2-[2-(cyclobutyloxy)pyridin-4-yl]phenol, (Preparation 862, 20.5mg, 0.000074 mol) was dissolved in dimethylsulphoxide (1 mL). Potassiumcarbonate (24.6 mg, 0.00018 mol) was added and the reaction stirred for10 minutes at room temperature.3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide,(Preparation 68, 32.2 mg, 0.000074 mol) was added and the reaction wasstirred at room temperature for 15 hours under nitrogen. The reactionwas partitioned between a saturated aqueous sodium chloride solution (10mL) and ethyl acetate (10 mL), the organic layer was washed with water(30 mL). The organic extracts were dried over anhydrous magnesiumsulphate, filtered and the solvent removed in vacuo to give a colourlessfoam (56 mg). The material was purified using an ISCO™ companion (4 gcolumn, eluting with 100% heptane to 7:3 heptane/ethyl acetate).Fractions containing product were combined and concentrated in vacuo toobtain the title compound as a colourless oil (45 mg).

LCMS Rt=1.98 minutes MS m/z=690 [M³⁵ClH]+

¹HNMR (CDCl₃) δ 1.61-1.73 (m, 1H), 1.79-1.88 (m, 1H), 2.06-2.18 (m, 2H),2.40-2.49 (m, 2H), 3.45 (s, 3H), 3.82 (s, 3H), 5.14-5.21 (m, 1H), 5.29(s, 2H), 6.11 (d, 1H), 6.35 (dd, 1H), 6.49 (d, 1H), 6.73 (m, 1H),7.00-7.02 (m, 1H), 7.07-7.10 (m, 2H), 7.47 (dd, 1H), 7.52 (d, 1H), 7.61(d, 1H), 7.68 (dd, 1H), 8.15 (d, 1H), 8.20 (s, 1H).

Preparation 862 4-Chloro-2-[2-(cyclobutyloxy)pyridin-4-yl]phenol

4-(5-Chloro-2-methoxyphenyl)-2-(cyclobutyloxy)pyridine, (Preparation863, 88 mg, 0.00030 mol) was dissolved in anhydrous dichloromethane (1mL) and cooled to 0° C. Boron tribromide (152 mg, 0.00061 mol) was addedand the solution stirred for 90 minutes, warming slowly to roomtemperature. The reaction was cooled to 0° C. and water (2 mL) added.The reaction was partitioned between ethyl acetate (300 mL) and water(50 mL). The organics were dried over anhydrous magnesium sulphate,filtered and the solvents removed in vacuo to give an off white residue(54 mg). The material was purified using an ISCO™ companion (4 g column,eluting with 100% dichloromethane to 95:5:0.5dichloromethane/methanol/0.880 aqueous ammonia solution). Fractionscontaining product were combined and concentrated in vacuo to obtain thetitle compound as a yellow residue (20 mg).

LCMS Rt=1.72 minutes, MS m/z=276 [M³⁵ClH]+

¹HNMR (CDCl₃) δ 1.64-1.76 (m, 1H), 1.82-1.91 (m, 1H), 2.13-2.23 (m, 2H),2.45-2.54 (m, 2H), 5.18-5.25 (m, 1H), 5.64 (s, 1H), 6.83 (m, 1H),6.90-6.94 (m, 1H), 6.98 (dd, 1H), 7.23-7.26 (m, 2H), 8.22 (dd, 1H).

Preparation 863 4-(5-Chloro-2-methoxyphenyl)-2-(cyclobutyloxy)pyridine

2-Chloro-4-(5-chloro-2-methoxyphenyl)pyridine (Preparation 864, 150 mg,0.00059 mol) and cyclobutanol (76.6 mg, 0.00106 mol) were dissolved in1,4-dioxane (2 mL). Potassium tert-butoxide (132 mg, 0.00118 mol) wasadded and the solution stirred at 101° C. for 15 hours. The reaction waspartitioned between ethyl acetate (15 mL) and a 10% aqueous solution ofcitric acid (10 mL). The organic layer was washed with water (10 mL)followed by a saturated aqueous sodium chloride solution (10 mL). Theorganics were dried over anhydrous magnesium sulphate, filtered and thesolvents removed in vacuo to give a yellow oil (195 mg). The materialwas purified using an ISCO™ companion (12 g column, eluting with 100%heptane to 7:3 heptane/ethyl acetate). Fractions containing product werecombined and concentrated in vacuo to obtain the title compound as acolourless oil (84 mg).

LCMS Rt=1.92 minutes, MS m/z=290 [M³⁵ClH]⁺

¹HNMR (CDCl₃) δ 1.64-1.76 (m, 1H), 1.81-1.90 (m, 1H), 2.12-2.23 (m, 2H),2.45-2.53 (m, 2H), 3.82 (s, 3H), 5.19-5.26 (m, 1H), 6.84-6.85 (m, 1H),6.90-6.94 (m, 1H), 7.00 (dd, 1H), 7.30-7.33 (m, 2H), 8.15 (dd, 1H).

Preparation 864 2-Chloro-4-(5-chloro-2-methoxyphenyl)pyridine

To a nitrogen purged aqueous solution of sodium carbonate (2M, 14 mL)and ethylene glycol dimethyl ether (25 mL) was added4-chloro-2-iodoanisole (2.50 g, 0.00931 mol), 2-chloropyridine-4-boronicacid (1.61 g, 0.0102 mol) and bis(triphenylphosphine)palladium (II)dichloride (327 mg, 0.00047 mol). The reaction mixture was warmed to 50°C. and stirred for 5 hours. Following LCMS analysis the reaction waswarmed to 75° C. and stirred for 5 hours before cooling to roomtemperature. The reaction was partitioned between ethyl acetate (100 mL)and a 10% w/v aqueous solution of citric acid (50 mL). The organic layerwas washed with water (50 mL), dried over anhydrous magnesium sulphate,filtered and the solvents removed in vacuo to give the crude product asan orange oil (2.95 g). The material was purified using an ISCO™companion (120 g column, eluting with 100% heptane to 7:3 heptane/ethylacetate). Fractions containing product were combined and concentrated invacuo to obtain the title compound as an off white solid (1.10 g).

LCMS Rt=1.74 minutes, MS m/z=254 [M³⁵ClH]⁺

¹HNMR (CDCl₃) δ 3.84 (s, 3H), 6.95 (d, 1H), 7.31 (d, 1H), 7.35-7.38 (m,2H), 7.49-7.50 (m, 1H), 8.41 (d, 1H).

Preparation 865 4-Chloro-2-[2-(dimethylamino)pyridin-4-yl]phenol

A mixture of 2-chloro-4-(5-chloro-2-methoxyphenyl)pyridine (Preparation866, 157 mg, 0.618 mmol), azetidine hydrochloride (120 mg, 1.2 mmol),and N,N-diisopropylethylamine (220 uL, 1.2 mmol) inN,N-dimethylacetamide (4.1 mL, 44 mmol) was heated 20 minutes at 170° C.under microwave irradiation. The reaction mixture was poured into waterand saturated aqueous ammonium chloride and extracted with ethyl acetate(3×). The combined organic layers were washed with water then brine,dried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was taken up in methylene chloride, concentrated ontodiatomaceous earth, and purified by automated flash chromatography (12 gSiO2, hexanes to 9:1 ethyl acetate-methanol). A single peak containingthe major products eluted from the column. The appropriate fractionswere concentrated in vacuo. The residue was dissolved in 1 mL ofdimethylsulfoxide, filtered through a plug of cotton, and purified byreverse-phase HPLC to afford4-chloro-2-[2-(dimethylamino)pyridin-4-yl]phenol as a tan solid (50 mg,33%) followed by 4-chloro-2-(2-chloropyridin-4-yl)phenol as a light pinksolid (24 mg, 16%). Unexpectedly4-chloro-2-[2-(dimethylamino)pyridin-4-yl]phenol was isolated as themain product and none of the intended product was isolated. Thispresumably occurred due to decomposition of the dimethylacetamide toprovide dimethylamine which reacted preferentially to give4-chloro-2-[2-(dimethylamino)pyridin-4-yl]phenol

4-chloro-2-[2-(dimethylamino)pyridin-4-yl]phenol:

LC/MS Rt=1.16 minutes, MS m/z 249 [M³⁵ClH]+

¹H NMR (d₆-DMSO): δ 10.49 (s, 1H), 7.98 (d, 1H), 7.55 (d, 1H), 7.38 (m,1H), 7.26 (br s, 1H), 7.14 (d, 1H), 7.02 (d, 1H), 3.23 (s, 6H).

4-chloro-2-(2-chloropyridin-4-yl)phenol:

LC/MS Rt=1.46 minutes, MS m/z 240 [M³⁵ClH]+

¹H NMR (d₆-DMSO): δ 10.36 (s, 1H), 8.43 (m, 1H), 7.72 (m, 1H), 7.64 (m,1H), 7.48 (d, 1H), 7.33 (m, 1H), 7.01 (d, 1H).

Preparation 866 2-Chloro-4-(5-chloro-2-methoxyphenyl)pyridine

A mixture of 4-chloro-2-iodo-1-methoxybenzene (542 mg, 2.02 mmol),(2-chloropyridin-4-yl)boronic acid (400 mg, 2 mmol), and sodiumcarbonate (860.2 mg, 8.116 mmol) in 1,4-dioxane (8.4 mL, 110 mmol) andwater (2.8 mL, 160 mmol) was sparged 5 minutes with argon.Tetrakis(triphenylphosphine)palladium(0) (139.9 mg, 0.1210 mmol) wasadded and the reaction vial was capped. The reaction mixture was heatedat 90° C. After 3 hours, the reaction mixture was cooled to ambienttemperature and poured into water. The mixture was extracted with ethylacetate (3×). The combined organic layers were washed with brine, driedover sodium sulfate, filtered and concentrated in vacuo. The residue wastaken up in methylene chloride, concentrated onto diatomaceous earth,and purified by automated flash chromatography (24 g SiO2, hexanes to3:1 hexanes-ethyl acetate) to afford the product as a light yellowpowder.

LC/MS Rt=1.78 minutes, MS m/z 254 [M³⁵ClH]+

Preparation 8675-chloro-N-(2,4-dimethoxybenzyl-1)-2-fluoro-4-{2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethyl)phenoxy}-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide

To a solution of2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethyl)phenol(Preparation 868, 2.069 g, 5.791 mmol) in dimethyl sulfoxide (34 mL) wasadded potassium carbonate (1.66 g, 12.0 mmol). After stirring for 10minutes,5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide(Preparation 247, 2.67 g, 5.78 mmol) was added. After stirring at roomtemperature for 16 hours, the reaction solution was diluted with ethylacetate and washed with water and brine. The organic layer was driedover anhydrous magnesium sulfate, filtered, and concentrated.Purification by automated flash column chromatography using a 0-100%ethyl acetate/hexanes gradient and a 40 g column gave the title compound(3.20 g, 69%) as a clear oil.

LC/MS Rt=1.98 minutes

MS m/z 647 [M³⁵Cl−DMB]⁻.

Preparation 8682-[3-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethyl)phenol

To a solution of4-bromo-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Preparation869, 18.95 g, 0.06864 mol) in 1,2-dimethoxyethane (175 mL) was addedaqueous potassium carbonate (2M in water, 68.0 mL, 0.123 mol) andtetrakis(triphenylphosphine)palladium(0) (6.34 g, 0.00549 mol). Thereaction was sparged 3 times with Argon and heated to 75° C. To this,[2-hydroxy-5-(trifluoromethyl)phenyl]boronic acid (Preparation 871,21.22 g, 0.103 mol) was added in four portions over six hours. Thereaction solution was heated for an additional 12 hours and then allowedto cool. The mixture was diluted with ethyl acetate, washed with waterand brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated. Purification by automated flash column chromatographyusing a 0-50% ethyl acetate/hexanes gradient and a 80 g column gave thetitle compound (13.2 g, 54%) as a yellow oil.

LC/MS Rt=1.71 minutes MS m/z 356 [M]−

¹H NMR (CDCl₃): δ 1.70 (m, 3H), 2.03 (m, 2H), 2.20 (m, 1H), 3.70 (m,1H), 4.11 (m, 1H), 5.44 (m, 1H), 6.80 (br s, 1H), 6.97 (m, 1H), 7.49 (m,2H), 7.79 (s, 1H).

Preparation 869 4-bromo-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazoleor 4-bromo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

A 5 L 3-neck flask, charged with 4-bromo-3-nitro-1H-pyrazole(Preparation 870, 136 g, 708 mmol), toluene (1100 mL), andtrifluoroacetic acid (2.63 mL, 34.1 mmol) was equipped with a mechanicalstirrer, temperature probe, and an addition funnel. The reaction mixturewas heated to 80° C. Dihydropyran (71.4 mL, 783 mmol) was added over 30minutes via addition funnel. The reaction mixture became morehomogeneous over the course of addition of dihydropyran. Within 30minutes after addition was complete, the reaction mixture washomogeneous. The addition funnel was replaced with a condenser, and thetemperature was increased to 110° C. After 21 hours, the reactionmixture was cooled and concentrated in vacuo to a brown solid. Theresidue was taken up in 1.5 L of ethyl acetate and washed successivelywith water (200 mL), saturated aqueous sodium bicarbonate (200 mL), andbrine (2×200 mL). The organic layer was dried over magnesium sulfate andconcentrated in vacuo to half the initial volume. The solution wastreated with activated charcoal, filtered through diatomaceous earth,and concentrated in vacuo to about half the volume with the bathtemperature set at about 40° C. The solution was transferred to a 1 LErlenmeyer flask, seeded with crystals from a previous batch, and cooledin the freezer. After 45 hours, the crystals were collected byfiltration, washed sparingly with cold ethyl acetate, and dried in vacuoto afford a light tan powder (73.03 g, 37%). The filtrate wasconcentrated to ˜100 mL, transferred to a 500 mL Erlenmeyer flask,seeded with crystals from a previous batch, and cooled in the freezer.After 3 days, the crystals were collected by filtration, washedsparingly with ethyl acetate then hexanes, and dried in vacuo to afforda second crop of product as a light tan powder (67.41 g, 35%). Only oneregioisomeric product was obtained as indicated by ¹H NMR analysis, butthe regioisomer was not determined.

LC/MS Rt=1.51 minutes MS m/z no molecular ion observed

¹H NMR (d₆-DMSO): δ 8.55 (s, 1H), 5.56 (m, 1H), 3.92 (m, 1H), 3.67 (m,1H), 1.99 (m, 3H), 1.68 (m, 1H), 1.56 (m, 2H).

Preparation 870 4-bromo-3-nitro-1H-pyrazole

A 1 L 3-neck flask equipped with a stir bar was charged with3-nitro-1H-pyrazole (41.3 g, 365 mmol), sodium acetate (36.0 g, 438mmol), and acetic acid (260 mL). The flask was fitted with a septum,addition funnel, and a temperature probe. Bromine (23 mL, 450 mmol) wasadded over 30 minutes via addition funnel to the reaction mixture; thetemperature increased to 40° C. over the course of bromine addition. Theheterogeneous reaction mixture became homogeneous as the reactionprogressed, with the exception of a few chunks of solid. As thetemperature of the reaction mixture fell, a precipitate formed. Thereaction mixture was poured into 1.2 L of ice and water and stirredvigorously. After 15 minutes, the solids were collected by filtrationand washed with several portions of water (500 mL total). The solidswere dried under vacuum to afford the product as a tan powder (49.67 g,71%).

LC/MS Rt=1.10 minutes MS m/z 190 [M-H]−

¹H NMR (d₆-DMSO): δ 8.35 (s, 1H).

-   Reference for synthesis of 3-nitro-1H-pyrazole: Klebe, K. J.;    Habraken, C. L. Synthesis, 1973, 294.

Preparation 871 [2-hydroxy-5-(trifluoromethyl)phenyl]boronic acid

To a suspension of 2-methoxy-5-(trifluoromethyl)phenylboronic acid(24.93 g, 0.1133 mol) in dichloromethane (150 mL) cooled to 0° C. wasadded dropwise boron tribromide (11.0 mL, 0.116 mol) over 30 minutes.After stirring for 5 hours, more boron tribromide (2.0 mL, 0.021 mol)was added. After stirring for 2 more hours, the reaction mixture wasadded to ice water and stirred for 20 minutes. The resulting whiteprecipitate was filtered and washed with water to give a white solidthat contained product. The layers of the filtrate were separated andextracted with dichloromethane (2×). The combined organics were driedover anhydrous magnesium sulfate, filtered, and concentrated to give awhite solid which also contained product. It was determined by NMR thatthere was some methyl ether remaining, so all the material recovered wassuspended in dichloromethane (100 mL) and cooled to 0° C. To this wasadded boron tribromide (7.0 mL, 0.074 mol) dropwise over 10 minutes andthen boron tribromide (1M in dichloromethane, 11.0 mL, 0.0110 mol)dropwise over 10 minutes. After stirring for 5 hours, the reaction wascomplete as indicated by TLC. The reaction mixture was added to icewater, filtered, and washed with water to provide product (15.24 g, 65%)as a white solid. The layers of the filtrate were separated andextracted with dichloromethane (2×) and 4:1 dichloromethane:isopropylalcohol. The combined organics were dried over anhydrous magnesiumsulfate, filtered, and concentrated to give additional product (5.7 g,24%) as a white solid.

LCMS Rt=1.55 minutes, MS m/z 205 [M]⁻

¹HNMR (d₆-DMSO): δ 6.61 (d, 1H), 7.41 (m, 1H), 7.72 (m, 1H).

Preparation 872 tert-butyl[(5-chloro-2-fluoro-4-{2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethyl)phenoxy}phenyl)sulfonyl]1,3-thiazol-4-ylcarbamate

To a solution of2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethyl)phenol(Preparation 868, 28.73 g, 80.41 mmol) in dimethyl sulfoxide (175 mL)was added potassium carbonate (22.3 g, 161 mmol). After stirring for 10minutes, tert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate(Preparation 453, 33.02 g, 80.37 mmol) was added. After stirring for 14hours at room temperature, additional potassium carbonate (4.7 g, 34mmol) and tert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (1.25g, 3.0 mmol) were added and the reaction mixture heated at 45° C. for 7hours. The mixture was allowed to cool, diluted with ethyl acetate, andwashed with water and brine. The organic layer was dried over anhydrousmagnesium sulfate, filtered, and concentrated. Purification by manualflash column chromatography using 25% ethyl acetate/hexanes and an 8×46cm column provided product as a yellow oil (40 g, 70%).

LC/MS Rt=1.90 minutes MS m/z 770 [M³⁵Cl+Na]⁺.

Preparation 873 tert-Butyl4-[4-(5-chloro-2-hydroxyphenyl)pyrimidin-2-yl]piperazine-1-carboxylate

tert-Butyl piperazine-1-carboxylate (24.0 mg, 0.125 mmol) was added to amixture of 4-chloro-2-(2-chloropyrimidin-4-yl)phenol (Preparation 874,30.1 mg, 0.125 mmol), and triethylamine (61.2 uL, 0.437 mmol) inisopropyl alcohol (0.2 mL, 3 mmol). The reaction mixture was stirred atambient temperature. After 18 hours, LC/MS analysis indicated thereaction was not complete. The reaction mixture was heated 30 minutes at70° C. then cooled to ambient temperature. The reaction mixture wasdiluted with ethyl acetate, washed with water then brine, dried oversodium sulfate, filtered, and concentrated to give the product as alight brown paste (50 mg, 100%).

LC/MS Rt=2.02 minutes, MS m/z 391 [M³⁵ClH]+

¹H NMR (d₆-DMSO): δ 8.52 (d, 1H), 8.03 (d, 1H), 7.46 (d, 1H), 7.40 (m,1H), 6.98 (d, 1H), 3.73 (m, 4H), 3.47 (m, 4H), 1.43 (s, 9H).

Preparation 874 4-Chloro-2-(2-chloropyrimidin-4-yl)phenol

A mixture of 2,4-dichloropyrimidine (0.765 g, 5.03 mmol),(5-chloro-2-hydroxyphenyl)boronic acid (0.568 g, 3.30 mmol), 2.0 Maqueous sodium carbonate (2.82 mL, 5.64 mmol), and 1,2-dimethoxyethane(8 mL, 80 mmol) was sparged for 10 minutes with argon.Tetrakis(triphenylphosphine)palladium(0) (0.217 g, 0.188 mmol) wasadded, and the resultant mixture was heated 4 hours at 85° C. Thereaction mixture was cooled to 0° C., quenched with saturated aqueousammonium chloride solution, and extracted with methylene chloride (3×).The combined organic layers were washed with brine, dried over sodiumsulfate, filtered, and concentrated in vacuo. The residue was purifiedby automated flash chromatography (12 g silica gel, hexanes to ethylacetate) to afford the product as a yellow solid (61.5 mg, 7%).Additional 4-chloro-2-(2-chloropyrimidin-4-yl)phenol was isolated as amixture of the desired product and unreacted 2,4-dichloropyrimidine (62mg, 50% purity by LC/MS).

LC/MS Rt=1.74 minutes, MS m/z 241 [M³⁵ClH]+

¹H NMR (d₆-DMSO): δ 11.21 (s, 1H), 8.81 (d, 1H), 8.28 (d, 1H), 8.00 (d,1H), 7.45 (m, 1H), 7.06 (d, 1H).

Preparation 8754-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-(methoxymethyl)-N-pyridazin-3-ylbenzenesulfonamideand4-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-[(3E)-2-(methoxymethyl)pyridazin-3(2H)-ylidene]benzenesulfonamide

The title compound was prepared by analogy with the method used forExample 815 using5-chloro-2,4-difluoro-N-(methoxymethyl)-N-pyridazin-3-ylbenzenesulfonamideand5-chloro-2,4-difluoro-N-[(3E)-2-(methoxymethyl)pyridazin-3(2H)-ylidene]benzenesulfonamide(Preparation 876) used as a mixture of two regioisomers and2-(2-aminopyridin-4-yl)-4-chlorophenol (Preparation 721). The productwas purified on silica gel (chloroform to 100% of 10% methanol inchloroform) to give the desired product as an inseparable mixture ofisomers (3:1 ratio).

Product LCMS Rt=1.39 (minor) & 1.43 min MS m/z 550 [MH]+

Preparation 8765-chloro-2,4-difluoro-N-(methoxymethyl)-N-pyridazin-3-ylbenzenesulfonamideand5-chloro-2,4-difluoro-N-[(3E)-2-(methoxymethyl)pyridazin-3(2H)-ylidene]benzenesulfonamide

Prepared according to the process of Preparation 716 using5-chloro-2,4-difluoro-N-pyridazin-3-ylbenzenesulfonamide (Preparation877). The reaction was purified on silica gel (hexane to 50%hexane-ethyl acetate) to give the desired product as a mixture of isomer(3:2 ratio) which were used as a mixture in subsequent reactions.

LCMS Rt=1.49 & 1.55 min MS m/z 350 [MH]+

Preparation 877 5-chloro-2,4-difluoro-N-pyridazin-3-ylbenzenesulfonamide

Pyridazin-3-amine (1.00 g, 10.5 mmol) and triethylenediamine (1.18 g,10.5 mmol) was added concurrently to a solution of5-chloro-2,4-difluorobenzenesulfonyl chloride (2.60 g, 10.5 mmol) inacetonitrile (50 mL, 1000 mmol). The reaction mixture was stirred for 18h then concentrated. The residue was dissolved in ethyl acetate (30 mL),washed with water, brine, dried over sodium sulfate and concentrated.The residue was purified on automated silica gel chromatography(chloroform to 50% of 10% methanol in chloroform) to give 800 mg of thedesired product as a yellow solid.

LCMS Rt=LCMS Rt=1.46 min, MS m/z 306 [MH]+

Preparation 878 tert-Butyl[(4-{2-[2-(azetidin-1-ylmethyl)pyridin-4-yl]-4-chlorophenoxy}-2,5-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate

tert-Butyl({4-[4-chloro-2-(2-formylpyridin-4-yl)phenoxy]-2,5-difluorophenyl}sulfonyl)1,3-thiazol-4-ylcarbamate,(Preparation 879, 0.36 g, 0.00059 mol) was dissolved in dichloromethane(3 mL) then azetidine hydrochloride (0.083 g, 0.00089 mol) was added andreaction allowed to stir at room temperature for 30 minutes. Sodiumtriacetoxyborohydride (0.144 g, 0.00068 mol) was added and the reactionstirred at room temperature for 18 hours. Saturated aqueous sodiumbicarbonate solution (5 mL) was added and the reaction stirred for 30minutes. The reaction was then passed through a phase separationcartridge and the isolated dichloromethane layer concentrated in vacuoto give the desired product as an orange foam (0.325 g.

LCMS Rt=1.16 minutes, MS m/z=649 [M³⁵ClH]⁺.

¹HNMR (CDCl₃) δ 1.32 (s, 9H), 2.12 (m, 2H), 3.30 (m, 4H), 3.75 (s, 2H),6.51 (m, 1H), 7.09 (d, 1H), 7.28 (dd, 1H), 7.46 (m, 3H), 7.53 (d, 1H),7.88 (m, 1H), 8.55 (d, 1H), 8.76 (d, 1H).

Preparation 879 tert-Butyl({4-[4-chloro-2-(2-formylpyridin-4-yl)phenoxy]-2,5-difluorophenyl}sulfonyl)1,3-thiazol-4-ylcarbamate

4-(5-Chloro-2-hydroxyphenyl)pyridine-2-carbaldehyde, (Preparation 880,0.3 g, 0.0013 mol) and tert-butyl1,3-thiazol-4-yl[(2,4,5-trifluorophenyl)sulfonyl]carbamate, (Preparation297, 0.456 g, 0.0012 mol) were dissolved in dimethyl sulfoxide (5 mL)and potassium carbonate (0.355 g, 0.0026 mol) was added and reactionallowed to stir at room temperature for 2 hours. Water (10 mL) was addedto the reaction, the resultant white precipitate was filtered off anddried in vacuo to give the title compound as a white solid (0.658 g).

LCMS Rt=1.73 minutes, MS m/z=608 [M³⁵ClH]⁺

¹HNMR (CD₃OD) δ 1.30 (s, 9H), 6.70 (m, 1H), 7.22 (d, 1H), 7.52 (m, 2H),7.60 (d, 1H), 7.61 (d, 1H), 7.76 (d, 1H), 7.85 (m, 1H), 8.51 (d, 1H),8.89 (d, 1H), 10.02 (s, 1H).

Preparation 880 4-(5-Chloro-2-hydroxyphenyl)pyridine-2-carbaldehyde

(5-Chloro-2-hydroxyphenyl) boronic acid (1.58 g, 0.00914 mol) wascombined with 4-bromopyridine-2-carbaldehyde (1.70 g, 0.0091 mol),bis(triphenylphosphine)palladium (II) chloride (0.321 g, 0.00046 mol)and potassium carbonate (3.16 g, 0.0228 mol) in a 5 mL microwave vial.1,4-dioxane (3 mL) and water (0.2 mL) were added and heated to 100° C.for 50 minutes in the microwave. The reaction was diluted with ethylacetate (30 mL) and water (20 mL), filtered, the organic phase wasseparated then dried over anhydrous sodium sulphate, concentrated invacuo and purified by flash column chromatography, ISCO™ (80 g column,eluting with 100% heptane to 50% v/v ethyl acetate in heptane) to givethe title compound as a beige solid (0.47 g).

LCMS Rt=1.39 minutes, MS m/z=234 [M³⁵ClH]⁺.

¹HNMR (CD₃OD) δ 6.92 (d, 1H), 7.23 (dd, 1H), 7.37 (d, 1H), 7.88 (dd,1H), 8.22 (d, 1H), 8.75 (d, 1H), 10.05 (s 1H).

Preparation 8814-[2-(1-Azetidin-3-yl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenoxyl]-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

tert-Butyl3-{5-[2-(2-cyano-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}phenoxy)-5-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}azetidine-1-carboxylate,(Preparation 882, 4.76 g, 0.00597 mol) was dissolved in dichloromethane(80 mL) and cooled in ice. Trifluoroacetic acid (10 mL) was added andthe solution was stirred whilst warming to room temperature over 18hours. The solvents were removed in vacuo and the residue was slurriedin methanol (80 mL) and then the methanol was removed in vacuo. This wasrepeated two more times. Finally the residue was again slurried inmethanol (80 mL) and the solid was removed by filtration. The filtratewas evaporated in vacuo to give a yellowish foam. Water (50 mL) wasadded, then 0.880 aqueous ammonia (5 mL) to give a white solid which wasfiltered off, washed with a little tert-butylmethylether and dried invacuo to give the title compound as a white solid (3.02 g).

LCMS Rt=1.28 minutes, MS m/z=548 [MH]+

¹HNMR (d₆-DMSO) δ 4.17-4.31 (m, 4H), 5.13 (m, 1H), 6.44 (s, 1H), 7.05(d, 1H), 7.54 (d, 1H), 7.72 (s, 1H), 7.86-8.05 (m, 5H).

Preparation 882 tert-Butyl3-{5-[2-(2-cyano-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}phenoxy)-5-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}azetidine-1-carboxylate

tert-Butyl3-{5-[2-hydroxy-5-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}azetidine-1-carboxylate,(Preparation 883, 2.20 g, 0.00574 mol), potassium carbonate (1.60 g,0.0116 mol) and3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide,(Preparation 68, 2.50 g, 0.00575 mol) were combined in a 50 mL roundbottomed flask and the flask was cooled in ice. Dimethylsulphoxide (15mL) was added and after a few minutes the ice bath was removed and thereaction was stirred at room temperature for 3 hours under nitrogen. Thereaction was diluted with water (50 mL) and extracted withtert-butylmethylether (100 mL) and the organic layer was washed withwater (30 mL). The organic extracts were dried over anhydrous sodiumsulphate, filtered and the solvent removed in vacuo to give the titlecompound as a white foam (4.76 g).

LCMS Rt=1.90 minutes, MS m/z=698 [M−BoCH]⁺

¹HNMR (CDCl₃) δ 1.45 (s, 9H), 3.52 (s, 3H), 3.82 (s, 3H), 4.28-4.48 (m,4H), 4.92 (m, 1H), 5.32 (s, 2H), 6.13 (m, 1H), 6.27 (m, 1H), 6.35 (m,1H), 6.52 (d, 1H), 7.08 (d, 1H), 7.19 (d, 1H), 7.63 (m, 2H), 7.69 (m,1H), 7.77 (d, 1H), 7.83 (m, 1H), 8.21 (s, 1H).

Preparation 883 tert-Butyl3-{5-[2-hydroxy-5-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}azetidine-1-carboxylate

To a stirred solution of crude tert-butyl3-hydrazinoazetidine-1-carboxylate, (Preparation 696, 5.7 g, 0.030 mol)in ethanol (66 mL) at 0° C. was added acetic acid (6.6 mL) dropwise.Then(2E)-3-(dimethylamino)-1-[2-hydroxy-5-(trifluoromethyl)phenyl]prop-2-en-1-one,(Preparation 859, 6.4 g, 24.68 m mol) was added portionwise and allowedto stir at room temperature for 20 hours. The reaction mixture wasconcentrated in vacuo and neutralised with aqueous sodiumhydrogencarbonate solution. The mixture was extracted with ethyl acetate(150 mL). The combined organic layer was washed with water (100 mL),saturated aqueous sodium chloride solution (50 mL) and dried overanhydrous sodium sulphate. After concentration of organic layer invacuo, the crude product was washed with 20% v/v ethyl acetate in hexaneto get the title compound as a white solid (7.4 g)

LCMS Rt=3.52 minutes, MS m/z=384 [MH]⁺

¹HNMR (CDCl₃) δ 1.45 (s, 9H), 4.27-4.37 (m, 3H), 4.70 (brs, 1H),4.79-4.83 (m, 1H), 6.25 (s, 1H), 7.16 (d, 1H), 7.46 (s, 1H), 7.55 (d,1H), 7.66 (s, 1H), 9.64 (s, 1H).

HPLC Purity: 99.84%

Preparation 884 5-Fluoro-2-pyridazin-4-yl-4-(trifluoromethyl)phenol

Cesium fluoride (570 mg, 3.8 mmol),tetrakis(triphenylphosphine)palladium(0) (220 mg, 0.19 mmol), andcopper(I) iodide (72 mg, 0.38 mmol) were added to a solution of5-fluoro-2-iodo-4-(trifluoromethyl)phenol (Preparation 885, 579 mg, 1.89mmol) and 4-(tributylstannyl)pyridazine (770 mg, 2.1 mmol) inN,N-dimethylformamide (4 mL, 50 mmol). The sides of the flask werewashed down with N,N-dimethylformamide (3 mL, 40 mmol). The flask wascapped with a septum then evacuated and back-filled with argon (5cycles). The reaction mixture was heated at 45° C. After 90 min, thereaction mixture was cooled to ambient temperature, diluted with ethylacetate and water, and filtered through diatomaceous earth. The solidswere washed with additional ethyl acetate. The layers were separated,and the organic layer was washed successively with water, aqueouslithium chloride, and brine. The organic layer was then dried oversodium sulfate, filtered, and concentrated in vacuo. The residue wastaken up in methylene chloride, concentrated onto diatomaceous earth,and purified by automated flash chromatography (24 g SiO2, methylenechloride to 9:1 methylene chloride-methanol) to afford the product as atan solid (305 mg, 62%).

LC/MS Rt=1.57 minutes, MS m/z 259 [MH]+

¹H NMR (d₆-DMSO): δ 11.74 (s, 1H), 9.49 (m, 1H), 9.26 (m, 1H), 7.93 (m,1H), 7.87 (d, 1H), 6.99 (d, 1H).

Preparation 885 5-Fluoro-2-iodo-4-(trifluoromethyl)phenol

A solution of iodine (0.874 g, 3.44 mmol) in chloroform (17.1 mL, 214mmol) was added over a period of 1.5 hours dropwise via addition funnelto a mixture of 3-fluoro-4-(trifluoromethyl)phenol (Preparation 886, 620mg, 3.4 mmol) and silver trifluoroacetate (0.760 g, 3.44 mmol) inchloroform (3.4 mL, 43 mmol). After addition was complete, the reactionmixture was stirred an additional 1 hour. The reaction mixture wasfiltered through diatomaceous earth, and the filtrate was washedsuccessively with 10% aqueous sodium thiosulfate (w/v), half-saturatedaqueous sodium bicarbonate, water and brine. The organic phase was driedover sodium sulfate, filtered, and concentrated onto diatomaceous earth.The residue was purified by automated flash chromatography (24 g SiO₂,hexanes to 1:1 methylene chloride-hexanes gradient elution). The initialproduct-containing fraction contained predominantly diiodinated material(by mass) with some monoiododinated material. The remaining fractionswere concentrated in vacuo to afford the product as a light yellow oil(579 mg, 54%). The product was not dried under vacuum due to volatility.

LC/MS Rt=1.79 minutes, MS m/z 305 [MH]−

¹H NMR (d₆-DMSO): δ 11.81 (s, 1H), 7.97 (d, 1H), 6.85 (d, 1H).

Preparation 886 3-Fluoro-4-(trifluoromethyl)phenol

A solution of OXONE® (1.50 g, 2.45 mmol) in water (7.8 mL, 430 mmol) wasadded over about 4 minutes dropwise to a solution of2-[3-fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(710 mg, 2.4 mmol) in acetone (7.8 mL, 110 mmol). A precipitate formedduring addition of the OXONE®. The reaction mixture was stirredvigorously for 15 minutes after addition was complete then quenched with20 mL of a 10% aqueous solution of sodium metabisulfite (w/v). Theaqueous layer was extracted with methylene chloride (3×), dried oversodium sulfate, filtered, and concentrated in vacuo to a light yellowoil. The product was advanced to the iodination reaction withoutpurification; 100% conversion to the phenol was assumed.

LC/MS Rt=1.65 minutes, MS m/z 179 [MH]−

Preparation 8874-{2-[3-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-chlorophenoxy}-5-chloro-2-fluoro-N-(methoxymethyl)-N-pyrimidin-4-ylbenzenesulfonamide

To a solution of5-chloro-4-(4-chloro-2-(3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenoxy)-2-fluoro-N-(methoxymethyl)-N-(pyrimidin-4-yl)benzenesulfonamide(80 mg, 0.1 mmol) in ethanol (4 mL, 70 mmol) was added saturated aqueousammonium chloride solution (0.4 mL, 6 mmol) and iron (328 mg, 5.87mmol). The reaction solution was heated at 80° C. for 20 minutes thenfiltered. Saturated aqueous sodium bicarbonate was added until the pHwas 9. The mixture was concentrated in vacuo to remove the ethanol.Water was added and the mixture was extracted three times withdichloromethane. The combined organic phase was dried over anhydroussodium sulfate, filtered, and concentrated in vacuo. The residue waspurified on silica gel (hexane to 100% ethyl acetate gradient) to give61 mg of a colorless oil.

LCMS Rt=1.97 min MS m/z 623 [MH]+

Preparation 888 2-pyridazin-4-yl-4-(trifluoromethoxy)phenol

The title compound was prepared according to the process of Preparation712 using 2-iodo-4-(trifluoromethoxy)phenol (Preparation 226).

LCMS Rt=1.62 minutes, MS m/z 257 [MH]+

¹HNMR (300 MHz, d₆-DMSO): δ 7.09 (d, 1H), 7.34 (m, 1H), 7.56 (d, 1H),7.92 (dd, 1H), 9.26 (dd, 1H), 9.49 (dd, 1H), 10.64 (s, 1H).

Preparation 889N-(2,4-dimethoxybenzyl)-2,4-difluoro-5-methyl-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide

The title compound was prepared according to the process of Preparation247 using 2,4-difluoro-5-methylbenzenesulfonyl chloride (Preparation890).

LCMS Rt=1.76 min, MS m/z 464 [MNa]+

¹HNMR (300 MHz, CDCl₃): δ 2.23 (s, 3H), 3.71 (s, 3H), 3.75 (s, 3H), 5.30(s, 2H), 6.28 (d, 1H), 6.35 (dd, 1H), 6.83 (t, 1H), 7.23 (d, 1H), 7.62(t, 1H), 8.80 (s, 1H)

Preparation 890 2,4-difluoro-5-methylbenzenesulfonyl chloride

Chlorosulfonic acid (5.2 mL, 0.078 mol) was added dropwise to a solutionof 2,4-difluorotoluene (4.00 g, 0.0312 mol) in chloroform (75 mL, 0.94mol). The reaction was stirred 2 hours. Additional chlorosulfonic acid(3.1 mL, 0.047 mol) was added and stirring was continued for 18 hours.The reaction was evaporated to an oil and poured onto ice. The mixturewas extracted two times with ethyl ether. The combined organic phase wasdried over magnesium sulfate and treated with activated carbon. Themixture was filtered through diatomaceous earth and the filtrate wasevaporated to give 5.31 g of light brown oil.

LCMS Rt=1.67 minutes, MS m/z not observed.

¹HNMR (300 MHz, CDCl₃): δ 2.34 (s, 3H), 7.02 (t, 1H), 7.23 (m, 2H), 7.84(t, 1H).

Preparation 8914-{2-[3-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-chlorophenoxy}-5-chloro-2-fluoro-N-(methoxymethyl)-N-pyridazin-3-ylbenzenesulfonamideand4-{2-[3-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-chlorophenoxy}-5-chloro-2-fluoro-N-[(3E)-2-(methoxymethyl)pyridazin-3(2H)-ylidene]benzenesulfonamide

The title compound was prepared using the method described inPreparation 887 using5-chloro-4-{4-chloro-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]phenoxy}-2-fluoro-N-(methoxymethyl)-N-pyridazin-3-ylbenzenesulfonamideand5-chloro-4-{4-chloro-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]phenoxy}-2-fluoro-N-[(3E)-2-(methoxymethyl)pyridazin-3(2H)-ylidene]benzenesulfonamide(Preparation 892). The product was a mixture of isomers.

LCMS Rt=1.84 min MS m/z 623 [MH]+

Preparation 8925-chloro-4-{4-chloro-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]phenoxy}-2-fluoro-N-(methoxymethyl)-N-pyridazin-3-ylbenzenesulfonamideand5-chloro-4-{4-chloro-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]phenoxy}-2-fluoro-N-[(3E)-2-(methoxymethyl)pyridazin-3(2H)-ylidene]benzenesulfonamide

The title compound was prepared using the method described inPreparation 893 using5-chloro-2,4-difluoro-N-(methoxymethyl)-N-pyridazin-3-ylbenzenesulfonamideand5-chloro-2,4-difluoro-N-[(3E)-2-(methoxymethyl)pyridazin-3(2H)-ylidene]benzenesulfonamide(Preparation 876) and4-chloro-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]phenol(Preparation 894). A mixture of isomers was present.

LCMS Rt=1.85 min MS m/z 653 [MH]+

Preparation 8935-chloro-4-{4-chloro-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]phenoxy}-2-fluoro-N-(methoxymethyl)-N-pyrimidin-4-ylbenzenesulfonamide

The title compound was prepared using the method described inPreparation 872 using5-chloro-2,4-difluoro-N-(methoxymethyl)-N-pyrimidin-4-ylbenzenesulfonamide(Preparation 895) and4-chloro-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]phenol(Preparation 894). The product was purified on silica gel (hexane to 50%of 60% ethyl acetate gradient) to provide 82 mg of a colorless oil.

LCMS Rt=1.92 min MS m/z 653 [MH]+

¹HNMR (d₆-DMSO): δ 1.45-1.73 (m, 3H), 1.76-2.06 (m, 3H), 3.35 (3H, s),3.63 (m, 1H), 3.81 (m, 1H), 5.42 (s, 2H), 5.52 (dd, 1H), 6.83 (d, 1H),7.37 (m, 2H), 7.59 (dd, 1H), 7.71 (d, 1H), 8.07 (d, 1H), 8.28 (s, 1H),8.69 (d, 1H), 8.80 (s, 1H).

Preparation 8944-chloro-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]phenol

(5-chloro-2-hydroxyphenyl)boronic acid (16.10 g, 93.38 mmol) and4-bromo-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole or4-bromo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Preparation869, 22.95 g, 83.12 mmol) in 1,2-dimethoxyethane (300 mL, 3000 mmol) and2 M of potassium carbonate in water (116 mL, 2.10E2 mmol) was addedtetrakis(triphenylphosphine)palladium(0) (5.0 g, 4.3 mmol). The solutionwas sparged 3 times with Ar and heated at 80° C. for 4 hours. Additional(5-chloro-2-hydroxyphenyl)boronic acid (2.866 g, 16.62 mmol) was addedto the reaction. The reaction was heated at 80° C. for another 18 hours.The cooled reaction was poured into a separatory funnel and the phasesseparated. The aqueous phase was washed two times with dichloromethane(250 mL). The combined organic phase was washed with brine then driedover anhydrous magnesium sulfate and treated with activated carbon. Themixture was filtered through diatomacious earth and the filtrateevaporated to a residue. The crude product was separated into twoportions and each purified by column chromatography (80 g silica gelcolumn, hexanes to 20% ethyl acetate gradient elution). Productfractions were combined and evaporated to give a thick oil which formeda waxy solid upon standing. The solid was triturated with hexanes andfiltered to give 17.71 g of tan powder after vacuum drying.

LCMS Rt=1.46 min MS m/z 322 [MH]−

¹HNMR (d₆-DMSO): δ 1.58-1.75 (m, 3H), 1.91-2.16 (m, 3H), 3.69 (m, 1H),3.95 (m, 1H), 5.55 (dd, 2H), 6.87 (d, 1H), 7.24 (dd, 1H), 7.34 (d, 1H),8.32 (s, 1H), 10.06 (s, 1H).

Preparation 8955-chloro-2,4-difluoro-N-(methoxymethyl)-N-pyrimidin-4-ylbenzenesulfonamideand5-chloro-2,4-difluoro-N-[(4E)-3-(methoxymethyl)pyrimidin-4(3H)-ylidene]benzenesulfonamideand5-chloro-2,4-difluoro-N-[(4E)-1-(methoxymethyl)pyrimidin-4(1H)-ylidene]benzenesulfonamide

5-chloro-2,4-difluoro-N-pyrimidin-4-ylbenzenesulfonamide (Preparation723, 0.80 g, 2.6 mmol) and N,N-diisopropylethylamine (0.68 mL, 3.9 mmol)in methylene chloride (20 mL, 300 mmol) at −78° C. was addedChloromethyl Methyl Ether (0.26 mL, 2.9 mmol). After stirring from −78°C. to room temperature for 20 hours, the reaction mixture was dilutedwith ethyl acetate, washed with 1N NaOH, water, brine, dried overanhydrous sodium sulfate, filtered and concentrated. The residue waspurified on silica gel (hexane to 100% ethyl acetate) to give threeisomers.

Isomer A: 467 mg

LCMS Rt=1.66 min MS m/z 350 [MH]+

¹HNMR (d₆-DMSO): δ 3.38 (s, 3H), 5.47 (s, 2H), 7.41 (dd, 1H), 7.88 (t,1H), 8.27 (t, 1H), 8.71 (d, 1H), 8.81 (s, 1H).

Isomer B: 187 mg

LCMS Rt=1.50 min MS m/z 350 [MH]+

¹HNMR (d₆-DMSO): δ 3.33 (s, 3H), 5.43 (s, 2H), 7.47 (d, 1H), 7.79 (t,1H), 8.09 (t, 1H), 8.30 (d, 1H), 8.89 (s, 1H).

Isomer C: 132 mg

LCMS Rt=1.12 min MS m/z 350 [MH]+

¹HNMR (d₆-DMSO): δ 3.28 (s, 3H), 5.26 (s, 2H), 6.77 (d, 1H), 7.69 (t,1H), 8.01 (t, 1H), 8.15 (dd, 1H), 8.69 (d, 1H).

Preparation 896 4-(5-trifluoro-2-methoxyphenyl)pyridazine

Method 1

4-(5-trifluoro-2-methoxyphenyl)pyridazine was prepared using a methodanalogous to that below for Preparation 897 using 4-bromopyridazinehydrobromide (Preparation 898) and the appropriate boronic acid, namely(5-trifluoro-2-methoxyphenyl)boronic acid. Purification using ISCO™(using a gradient of 0-80% ethyl acetate in heptane, 12 g SiO₂) affordedthe title compound.

LCMS Rt=1.46 min MS m/z 255 [MH]+

¹H NMR (400 MHz, d₆-DMSO): δ 3.90 (s, 3H), 7.70 (m, 1H), 7.85 (m, 3H),9.30 (m, 1H), 9.45 (s, 1H)

Method 2

4-(5-trifluoro-2-methoxyphenyl)pyridazine can also be prepared accordingto the following procedure:

To a solution of acetic anhydride (1 mL) and acetic acid (2 mL) wasadded potassium acetate (517 mg, 5.28 mmol) and the mixture stirreduntil dissolution. The solution was then cooled to 0° C. using an icebath and bromine (68 μL, 1.32 mmol) added followed by the bromofuran(194 mg, 1.32 mmol). The reaction turned pale yellow and was allowed tostir at 0° C. for 30 minutes before warming to room temperature. Thereaction was concentrated in vacuo, azeotroping with toluene (2×5 mL).The resulting solid was slurried in 1,4-dioxane (5 mL) and hydrazinehydrate (320 μL, 6.60 mmol) was added. The reaction was stirred at roomtemperature for 1 hour before the addition of cesium carbonate (860 mg,2.64 mmol), (5-trifluoro-2-methoxyphenyl)boronic acid (290 mg, 1.32mmol) and palladium tetrakistriphenylphosphine (152 mg, 0.132 mmol). Thereaction was heated to 70° C. under nitrogen for 3 hours. The reactionwas cooled and concentrated in vacuo to afford the crude title compound.

LCMS Rt=1.46 min MS m/z 255 [MH]+

Preparation 897 4-[2-(benzyloxy)-5-(trifluoromethyl)phenyl]pyridazine

([2-(benzyloxy)-5-(trifluoromethyl)phenyl]boronic acid (3.72 g, 0.0126mol) and caesium carbonate (8.9 g, 0.0273 mol) were suspended in 1,4dioxane (40.0 mL) and water (20.0 mL). The reaction was degassed twicebefore being brought to 80° C. under nitrogen. Then 4-bromopyridazinehydrobromide (Preparation see above, 2.52 g, 0.0105 mol) and palladiumtetrakistriphenylphosphine (0.62 g, 0.000537 mol) were added to thereaction and it was stirred for three hours. The reaction wasconcentrated in vacuo to 20.0 mL, and partitioned between ethyl acetate(70.0 mL) and saturated aqueous brine (50.0 mL). The two layers werefiltered over Arbocel™ to remove a fine black solid. Then the organiclayer was washed with more saturated aqueous brine (2×50.0 mL) and itwas dried over sodium sulphate. The solvents were concentrated in vacuoand crude was purified using ISCO™ (using a gradient of 0-50% ethylacetate in heptane, 80 g SiO₂) to afford the title compound as a lightorange solid.

LCMS Rt=1.67 minutes

MS m/z 331 [MH]+

¹H NMR (400 MHz, d₆-DMSO): δ 5.25 (s, 2H), 7.35-7.45 (m, 5H), 7.50 (d,1H), 7.85 (m, 1H), 7.90 (t, 1H), 9.25 (d, 1H), 9.45 (s, 1H)

Preparation 898 4-bromopyridazine hydrobromide

3-Bromofuran (5.0 g, 0.034 mol) and potassium acetate (9.2 g, 0.0937mol) were suspended in acetic acid (30.0 mL). Bromine (1.75 mL, 0.0342mol) in acetic acid (10.0 mL) was then added drop wise and the reactionstirred for one hour. The reaction was filtered and the filtrateconcentrated in vacuo. The residue was dissolved in ethanol (50.0 mL)and hydrazine hydrate (5.0 mL, 0.103 mol) was added drop wise to thesolution, which was stirred at room temperature for two hours. Thereaction was diluted in ethyl acetate (100.0 mL) and washed with asolution of saturated aqueous brine (100.0 mL). The organic layer wascollected and washed once more with a solution of saturated aqueousbrine (100.0 mL). The aqueous layer was extracted with ethyl acetate(50.0 mL) and the organic layers were combined, then dried over sodiumsulfate, filtered, and concentrated in vacuo. The resulting residue wasdissolved in 1,4 dioxane (25 mL) and hydrobromic acid in acetic acid (5mL) was added drop wise. The resulting brown solid was filtered, thensuspended in acetone (25 mL), subjected to a sonication bath and finallyfiltered again. Title compound was isolated as a brown solid (5.95 g,73% yield).

LCMS Rt=0.75 minutes MS m/z 159 [M⁷⁹BrH]+

¹H NMR (400 MHz, d₆-DMSO): δ 8.10 (m, 1H), 7.80-8.80 (br s, 1H), 9.10(d, 1H), 9.45 (s, 1H)

Preparation 899 2-(3-Furyl)-4-(trifluoromethyl)phenyl acetate

2-Iodo-4-(trifluoromethyl)phenol (9.9 g, 0.0344 mol) was dissolved in2-methyl tetrahydrofuran (100 mL) then potassium acetate (11.8 g, 0.12mol) and 3-furylboronic acid (5.0 g, 0.0447 mol) was added and thereaction degasses 3 times before bis(tri-tert-butylphosphine) palladium(0) (1.0 g, 0.00196 mol) was added and the reaction degassed 3 moretimes. The reaction was then stirred at 90° C. under nitrogen for 18hours. The reaction was then cooled and partitioned between EtOAc (50mL) and water (50 mL), the organic layer was separated and dried invacuo to give a brown oil. This was dissolved in tert-butyl methyl ether(50 mL), triethylamine (7.2 mL, 0.051 mol) added then acetic anhydride(4.7 mL, 0.051 mol) and stirred for 2 hours at room temperature. Thereaction was then partitioned between EtOAc (30 ml) and water (30 ml)then organic layer was dried in vacuo to give a brown oil whichcrystallised upon standing. This was triturated with heptane to give thetitle product as a pale brown solid (8.04 g, 86.6%). LCMS Rt=1.70 min.¹H NMR (400 MHz, CDCl₃): δ 2.34 (s, 3H), 6.67 (s, 1H) 7.26 (m, 1H) 7.51(s, 1H), 7.57 (d, 1H), 7.76 (m 2H)

Preparation 9005-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-[2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide

5-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide(Preparation 247, 378.0 g, 0.761 moles) was dissolved indimethylsulphoxide (1.9 L). Potassium carbonate (117.8 g, 0.8524 moles)was added and stirred to give a suspension to which was added2-pyridazin-4-yl-4-(trifluoromethyl)phenol (Preparation 712, 182.8 g,0.761 moles) in one portion. The reaction mixture was stirred at roomtemperature for 18 hours. The reaction mixture was partitioned betweenethyl acetate (2.7 L) and aqueous sodium hydroxide solution (2.5 L of 1molar). The organic phase was washed with water (2×2 L) and thensaturated aqueous sodium chloride solution (250 mL). The solution wasconcentrated in vacuo to give the crude title product. The crude productwas purified by column chromatography on silica gel (2 Kg) eluting withethyl acetate/heptane (3:1). The cleanest fractions were combined andthe solvents removed in vacuo to give the title compound as a dark redfoam, (440 g). This material was dried in vacuo at 45° C. for 48 hoursto give the title compound as a red solid (400 g).

LCMS Rt=1.81 minutes. MS m/z 682 [MH]+ and 704 [M+Na]+

¹HNMR (d₆-DMSO): δ 3.65 (s, 3H), 3.70 (s, 3H), 5.14 (s, 2H), 6.41-6.45(m, 2H), 7.10 (d, 1H), 7.37 (d, 1H), 7.54 (d, 1H), 7.88-7.99 (m, 3H),8.17 (s, 1H), 9.83 (s, 1H), 9.86 (d, 1H), 9.51 (m, 1H).

The ability of the compounds of the formula (I) to block the Nav1.7 (orSCN9A) channel were measured using the assay described below.

Cell Line Construction and Maintenance

Human Embryonic Kidney (HEK) cells were transfected with an hSCN9Aconstruct using lipofectamine reagent (Invitrogen), using standardtechniques. Cells stably expressing the hSCN9A constructs wereidentified by their resistance to G-418 (400 μg/ml). Clones werescreened for expression using the whole-cell voltage-clamp technique.

Cell Culture

HEK cells stably transfected with hSCN9A were maintained in DMEM mediumsupplemented with 10% heat-inactivated fetal bovine serum and 400 μg/mlG-418 in an incubator at 37° C. with a humidified atmosphere of 10% CO₂.For HTS, cells were harvested from flasks by trypsinization and replatedin an appropriate multi-well plate (typically 96 or 384 wells/plate)such that confluence would be achieved within 24 hours of plating. Forelectrophysiological studies, cells were removed from the culture flaskby brief trypsinization and re-plated at low density onto glass coverslips. Cells were typically used for electrophysiological experimentswithin 24 to 72 hours after plating.

Electrophysiological Recording

Cover slips containing HEK cells expressing hSCN9A were placed in a bathon the stage of an inverted microscope and perfused (approximately 1ml/minutes) with extracellular solution of the following composition:138 mM NaCl, 2 mM CaCl₂, 5.4 mM KCl, 1 mM MgCl₂, 10 mM glucose, and 10mM HEPES, pH 7.4, with NaOH. Pipettes were filled with an intracellularsolution of the following composition: 135 mM CsF, 5 mM CsCl, 2 mMMgCl₂, 10 mM EGTA, 10 mM HEPES, pH 7.3 with NaOH, and had a resistanceof 1 to 2 megaohms. The osmolarity of the extracellular andintracellular solutions was 300 mOsm/kg and 295 mOsm/kg, respectively.All recordings were made at room temperature (22-24° C.) using AXOPATCH200B amplifiers and PCLAMP software (Axon Instruments, Burlingame,Calif.).

hSCN9A currents in HEK cells were measured using the whole-cellconfiguration of the patch-clamp technique (Hamill et al., 1981).Uncompensated series resistance was typically 2 to 5 mega ohms and >85%series resistance compensation was routinely achieved. As a result,voltage errors were negligible and no correction was applied. Currentrecords were acquired at 20 to 50 KHz and filtered at 5 to 10 KHz.

HEK cells stably transfected with hSCN9A were viewed under Hoffmancontrast optics and placed in front of an array of flow pipes emittingeither control or compound-containing extracellular solutions. Allcompounds were dissolved in dimethyl sulfoxide to make 10 mM stocksolutions, which were then diluted into extracellular solution to attainthe final concentrations desired. The final concentration of dimethylsulfoxide (<0.3% dimethyl sulfoxide) was found to have no significanteffect on hSCN9A sodium currents.

The voltage-dependence of inactivation was determined by applying aseries of depolarizing prepulses (8 sec long in 10 mV increments) from anegative holding potential. The voltage was then immediately stepped to0 mV to assess the magnitude of the sodium current. Currents elicited at0 mV were plotted as a function of prepulse potential to allowestimation of the voltage at which 50% of the channels were inactivated(midpoint of inactivation or V1/2). Compounds were tested for theirability to inhibit hSCN9A sodium channels by activating the channel witha 20 msec voltage step to 0 mV following an 8 second conditioningprepulse to the empirically determined V1/2. Compound effect (%inhibition) was determined by difference in current amplitude before andafter application of test compounds. For ease of comparison, “estimatedIC-50” values were calculated from single point electrophysiology databy the following equation, (tested concentration, uM)×(100-% inhibition% inhibition). Inhibition values <20% and >80% were excluded from thecalculation.

In some cases electrophysiological assays were conducted withPatchXpress 7000 hardware and associated software (Molecular DevicesCorp). All assay buffers and solutions were identical to those used inconventional whole-cell voltage clamp experiments described above.hSCN9A cells were grown as above to 50%-80% confluency and harvested bytrypsinization. Trypsinized cells were washed and resuspended inextracellular buffer at a concentration of 1×10⁶ cells/ml. The onboardliquid handling facility of the PatchXpress was used for dispensingcells and application of test compounds. Determination of the voltagemidpoint of inactivation was as described for conventional whole-cellrecordings. Cells were then voltage-clamped to the empiricallydetermined V1/2 and current was activated by a 20 msec voltage step to 0mV.

Electrophysiological assays were also conducted using the IonworksQuattro automated electrophysiological platform (Molecular DevicesCorp). Intracellular and extracellular solutions were as described abovewith the following changes, 100 μg/ml amphotericin was added to theintracellular solution to perforate the membrane and allow electricalaccess to the cells. hSCN9A cells were grown and harvested as forPatchXpress and cells were resuspended in extracellular solution at aconcentration of 3−4×10⁶ cells/ml. The onboard liquid handling facilityof the Ionworks Quattro was used for dispensing cells and application oftest compounds. A voltage protocol was then applied that comprised of avoltage step to fully inactivate the sodium channels, followed by abrief hyperpolarized recovery period to allow partial recovery frominactivation for unblocked sodium channels, followed by a testdepolarized voltage step to assess magnitude of inhibition by testcompound. Compound effect was determined based on current amplitudedifference between the pre-compound addition and post-compound additionscans. The ability of the compounds of the formula (I) to block theNav1.5 (or SCN5A) channel can also be measured using an assay analogousto that described above but replacing the SCN9A gene with the SCN5Agene. All other conditions remain the same including the same cell lineand conditions for cell growth. The estimated IC50s are determined atthe half inactivation for Nav1.5. These results can be compared to theEIC₅₀ value at the Nav1.7 channel to determine the selectivity of agiven compound for Nav1.7 vs Nav1.5.

Compounds of the Examples were tested in the assay described above usingthe PatchXpress platform and found to have the EIC₅₀ values specified inthe table below.

SCN9A SCN9A SCN9A SCN9A EIC50 EIC50 EIC50 EIC50 Eg No (μM) Eg No (μM) EgNo (μM) Eg No (μM) 1 0.09 76 >10 151 0.05 226 0.03 2 0.81 77 0.36 1520.08 227 0.03 3 0.10 78 0.60 153 0.06 228 0.57 4 1.71 79 0.45 154 0.13229 0.12 5 0.07 80 >0.3 155 0.85 230 0.71 6 >1 81 0.51 156 0.03 231 0.477 35.92 82 37.19 157 0.45 232 1.87 8 0.45 83 2.45 158 0.31 233 3.49 93.50 84 >10 159 0.08 234 0.09 10 0.63 85 1.43 160 0.06 235 0.76 11 0.4386 1.88 161 0.07 236 13.93 12 0.72 87 1.60 162 0.42 237 0.21 13 0.17 880.27 163 0.41 238 2.21 14 4.30 89 0.68 164 0.58 239 1.90 15 0.84 90 0.10165 0.05 240 1.98 16 12.51 91 1.12 166 1.81 241 1.47 17 25.49 92 1.81167 0.75 242 0.12 18 >10 93 1.57 168 0.07 243 3.86 19 0.72 94 2.18 1690.05 244 1.79 20 >10 95 >10 170 0.01 245 1.04 21 >10 96 12.54 171 0.11246 3.76 22 3.14 97 2.32 172 0.07 247 2.95 23 2.03 99 >10 173 2.09 2482.78 24 0.11 99 24.94 174 >10 249 2.40 25 0.02 100 3.17 175 0.54 2501.85 26 0.45 101 1.58 176 8.87 251 2.54 27 0.78 102 >10 177 0.10 25224.47 28 2.98 103 1.30 178 3.08 253 0.63 29 0.23 104 2.25 179 2.19 2540.34 30 0.30 105 2.67 180 0.09 255 0.49 31 16.21 106 4.16 181 >10 2560.22 32 3.38 107 12.21 182 0.93 257 2.20 33 0.38 108 >10 183 0.99 2581.02 34 0.09 109 5.68 184 9.17 259 16.53 35 12.71 110 4.27 185 32.99 26015.88 36 1.29 111 >3 186 1.05 261 0.47 37 30.90 112 33.74 187 1.67 2621.32 38 15.53 113 12.86 188 9.42 263 1.44 39 2.03 114 >10 189 2.80 2642.38 40 5.74 115 >10 190 7.71 265 38.90 41 10.87 116 3.11 191 >10 2660.10 42 1.73 117 19.23 192 2.05 267 0.19 43 21.70 118 18.45 193 1.23 2683.06 44 5.93 119 17.67 194 36.85 269 0.48 45 30.44 120 37.35 195 1.08270 0.03 46 0.21 121 32.32 196 0.03 271 1.15 47 0.67 122 4.54 197 1.13272 0.81 48 0.90 123 9.20 198 2.47 273 2.17 49 0.16 124 15.06 199 0.11274 >10 50 0.84 125 22.96 200 0.10 275 0.07 51 0.33 126 11.49 201 0.42276 0.55 52 0.36 127 >10 202 0.60 277 1.11 53 3.54 128 3.11 203 7.48 2782.66 54 0.26 129 0.70 204 3.14 279 0.07 55 0.92 130 9.19 205 0.33 2800.09 56 0.38 131 12.12 206 1.19 281 0.12 57 0.66 132 17.28 207 1.03 2820.18 58 0.34 133 11.59 208 0.13 — — 59 2.28 134 3.77 209 0.59 — — 602.79 135 0.73 210 1.37 — — 61 25.70 136 2.70 211 0.11 — — 62 3.98 1372.59 212 15.41 — — 63 2.35 138 38.71 213 1.60 — — 64 0.78 139 5.00 2142.41 — — 65 12.21 140 3.41 215 6.44 — — 66 2.66 141 1.23 216 0.91 — — 674.22 142 2.62 217 0.51 — — 68 0.77 143 >10 218 0.23 — — 69 36.08 1441.39 219 0.02 — — 70 0.11 145 2.00 220 0.15 — — 71 12.46 146 0.89 2210.45 — — 72 >0.3 147 1.51 222 0.06 — — 73 23.43 148 2.53 223 1.51 — — 741.11 149 0.92 224 0.77 — — 75 3.34 150 0.19 225 0.43 — —

Yet further compounds of the Examples were also tested as describedabove and found to have the EIC₅₀ values specified in the table below.

SCN9A SCN9A SCN9A SCN9A Eg EIC50 Eg EIC50 Eg EIC50 Eg EIC50 No (μM) No(μM) No (μM) No (μM) 283 0.58 421 12 559 0.0007 697 0.0014 284 1.6422 >1 560 0.078 698 0.096 285 0.62 423 25 561 0.38 699 0.14 286 0.53424 >3 562 0.017 700 0.057 287 >1 425 11 563 0.13 701 0.30 288 >1 426 36564 0.0092 702 0.23 289 0.39 427 4.3 565 54 703 0.19 290 2.0 428 >10566 >30 704 0.011 291 2.5 429 >10 567 No data 705 0.015 292 0.044 430 12568 >3 706 0.026 293 0.093 431 11 569 >3 707 0.12 294 0.034 432 >10 5708.6 708 0.40 295 0.13 433 15 571 10 709 0.014 296 0.025 434 18 572 >30710 0.088 297 1.0 435 2.7 573 7.3 711 0.040 298 0.14 436 1.3 574 >3 7121.2 299 0.020 437 0.056 575 >30 713 0.0024 300 0.039 438 0.017 576 >3714 0.19 301 0.28 439 0.49 577 11 715 0.21 302 0.16 440 0.017 578 5.5716 0.43 303 0.43 441 0.96 579 >3 717 >0.30 304 0.025 442 1.3 580 6.9718 0.033 305 0.097 443 1.8 581 >3 719 0.16 306 >1 444 9.9 582 0.034 7200.056 307 0.81 445 >1 583 0.013 721 0.16 308 0.98 446 2.3 584 0.097 7220.14 309 0.025 447 1.8 585 0.097 723 0.064 310 >1 448 2.0 586 0.14 7240.0017 311 4.9 449 3.1 587 0.20 725 0.020 312 0.017 450 3.4 588 0.12 7260.0058 313 0.47 451 >1 589 0.51 727 1.9 314 0.73 452 3.3 590 0.053 7280.0048 315 1.2 453 1.7 591 0.073 729 0.022 316 0.74 454 >1 592 0.22 7300.0099 317 2.2 455 2.3 593 0.035 731 0.0073 318 1.3 456 1.9 594 0.16 7320.0035 319 2.5 457 2.0 595 0.080 733 0.010 320 3.3 458 0.74 596 0.079734 0.053 321 0.77 459 0.84 597 0.020 735 1.00 322 0.55 460 0.015 5980.23 736 0.0027 323 >0.30 461 0.020 599 0.30 737 0.017 324 >1 462 51 60015 738 0.0014 325 >0.30 463 22 601 0.94 739 0.15 326 2.1 464 6.0 602 1.5740 0.40 327 0.37 465 1.0 603 4.6 741 0.0078 328 0.081 466 36 604 0.82742 0.0036 329 0.34 467 0.0096 605 0.10 743 0.012 330 0.25 468 0.029 6060.13 744 0.17 331 2.0 469 3.3 607 2.8 745 0.12 332 >1 470 3.4 608 0.40746 0.095 333 >1 471 2.7 609 1.7 747 0.050 334 3.4 472 0.97 610 >1 7480.17 335 0.032 473 0.072 611 0.52 749 0.045 336 2.2 474 0.044 612 0.54750 0.21 337 2.5 475 0.0075 613 0.11 751 0.013 338 1.8 476 0.17 614 0.18752 0.0021 339 15 477 0.016 615 2.0 753 0.0052 340 34 478 0.044 616 0.28754 0.0053 341 3.6 479 0.23 617 0.030 755 0.0024 342 18 480 >1 618 0.011756 0.011 343 >10 481 1.7 619 0.045 757 0.0009 344 1.0 482 >1 620 0.0048758 0.21 345 14 483 >1 621 0.075 759 0.25 346 0.77 484 >1 622 >1 7600.088 347 0.30 485 >1 623 0.046 761 5.4 348 0.82 486 >1 624 0.057 7620.0042 349 >1 487 >1 625 0.018 763 0.034 350 0.015 488 >1 626 0.12 7640.030 351 0.018 489 1.2 627 0.16 765 0.11 352 0.19 490 0.66 628 1.0 7660.50 353 0.22 491 >1 629 0.24 767 0.24 354 0.18 492 1.5 630 >1 768 11355 0.40 493 0.58 631 3.3 769 8.7 356 0.12 494 2.5 632 0.10 770 24 3570.39 495 >1 633 0.027 771 0.24 358 0.36 496 3.8 634 0.011 772 31 3590.011 497 >1 635 0.0063 773 0.0069 360 0.33 498 0.030 636 0.0084 774 >1361 0.48 499 0.19 637 0.016 775 0.088 362 1.5 500 0.088 638 0.0048 7762.5 363 0.24 501 0.040 639 6.9 777 1.3 364 0.48 502 0.022 640 1.00 7780.47 365 0.069 503 0.007 641 1.3 779 0.21 366 4.8 504 0.0049 642 2.6 7800.032 367 2.4 505 0.050 643 2.1 781 0.022 368 >1 506 0.011 644 2.6 7820.009 369 0.49 507 0.011 645 >1 783 0.0078 370 1.6 508 0.020 646 2.8 7840.010 371 1.8 509 0.031 647 2.9 785 0.040 372 2.6 510 0.077 648 1.6 7860.0076 373 >1 511 0.0084 649 0.93 787 0.0072 374 1.9 512 3.4 650 1.6 7880.0086 375 >1 513 0.036 651 1 789 0.0021 376 >1 514 1.1 652 0.90 7900.0012 377 >1 515 1.9 653 1.1 791 0.0037 378 >1 516 10 654 1.1 792 0.011379 >1 517 2.2 655 0.049 793 0.0031 380 0.20 518 >1 656 0.27 794 0.0048381 0.47 519 1.2 657 0.083 795 0.0046 382 0.050 520 >1 658 0.25 7960.0021 383 0.31 521 2.9 659 0.091 797 0.0024 384 0.35 522 7.3 660 0.034798 0.0049 385 0.067 523 2.6 661 0.077 799 0.0088 386 0.091 524 0.58 6620.033 800 0.052 387 0.14 525 0.37 663 0.13 801 0.0013 388 0.74 526 0.16664 0.26 802 0.0098 389 1.1 527 0.14 665 >1 803 0.0048 390 0.30 528 0.74666 0.27 804 0.0012 391 0.0025 529 0.53 667 3.1 805 0.0062 392 0.14 5300.23 668 0.053 806 0.0054 393 0.99 531 1.1 669 0.20 807 0.015 394 2.9532 2.9 670 0.35 808 0.007 395 1.8 533 0.78 671 0.26 809 0.038 396 >3534 0.50 672 2.5 810 0.0038 397 >1 535 0.17 673 0.69 811 0.0026 398 >1536 0.22 674 0.088 812 0.0051 399 1.2 537 0.025 675 0.37 813 0.030 4001.2 538 3.4 676 0.19 814 0.0062 401 2.7 539 1.1 677 0.012 — — 402 0.25540 4.0 678 0.26 — — 403 0.0045 541 0.14 679 0.031 — — 404 1.2 542 0.066680 1.0 — — 405 0.0027 543 0.066 681 1.2 — — 406 3.0 544 0.022 682 0.71— — 407 0.19 545 0.023 683 0.022 — — 408 0.30 546 0.020 684 1.0 — — 4090.019 547 0.12 685 0.13 — — 410 0.029 548 0.41 686 0.33 — — 411 0.54 5490.16 687 0.080 — — 412 0.0025 550 0.20 688 5.1 — — 413 12 551 0.071689 >0.30 — — 414 1.0 552 0.0024 690 0.11 — — 415 >1 553 0.0017 691 0.43— — 416 1.6 554 0.12 692 0.11 — — 417 0.0085 555 0.014 693 0.081 — — 4182.3 556 0.0023 694 0.48 — — 419 2.1 557 0.0008 695 0.34 — — 420 24 5580.039 696 0.078 — —

Even further compounds of the Examples were also tested as describedabove and found to have the EIC₅₀ values specified in the table below.

SCN9A SCN9A SCN9A SCN9A Eg EIC50 Eg EIC50 Eg EIC50 Eg EIC50 No (μM) No(μM) No (μM) No (μM) 815 0.0006 876 >1 937 0.019 998 0.056 816 0.011 8770.47 938 0.025 999 3.3 817 0.3 878 0.0058 939 0.048 1000 0.13 818 0.32879 0.007 940 0.031 1001 0.82 819 2.4 880 0.11 941 0.072 1002 0.14 8200.23 881 0.26 942 0.035 1003 0.02 821 0.1 882 0.04 943 0.077 1004 7.1822 0.0078 883 14 944 0.031 1005 >3 823 0.0074 884 0.036 945 0.099 1006No data 824 0.0047 885 6.3 946 0.23 1007 3.3 825 0.19 886 6.2 947 0.0231008 0.74 826 0.3 887 9 948 0.011 1009 0.021 827 0.017 888 0.92 9490.087 1010 0.82 828 0.012 889 0.67 950 2.7 1011 0.028 829 0.034 8900.0094 951 0.04 1012 0.27 830 0.023 891 0.78 952 0.032 1013 0.0048 8310.063 892 >10 953 0.11 1014 0.01 832 0.42 893 3.8 954 0.24 1015 No data833 0.0059 894 >10 955 0.076 1016 No data 834 0.0039 895 >30 956 0.131017 0.0021 835 0.0021 896 0.34 957 0.022 1018 0.23 836 0.04 897 0.0058958 0.0059 1019 0.022 837 0.0058 898 0.0051 959 0.022 1020 0.019 8380.0018 899 0.018 960 0.004 1021 1.3 839 0.13 900 0.0028 961 0.0079 10220.0037 840 0.052 901 0.32 962 0.0099 1023 0.004 841 0.011 902 0.0023 9630.015 1024 0.019 842 0.096 903 0.32 964 0.021 1025 0.0041 843 0.034 9040.39 965 0.025 1026 0.0016 844 0.0073 905 0.19 966 0.04 1027 0.013 8450.041 906 0.057 967 0.027 1028 0.0031 846 0.23 907 >10 968 2 1029 0.005847 0.13 908 0.78 969 0.0041 1030 0.0007 848 0.0051 909 0.0021 970 0.0171031 0.029 849 0.12 910 0.012 971 0.0085 1032 0.013 850 0.0032 911 0.17972 0.025 1033 0.0035 851 0.0097 912 0.014 973 0.025 1034 0.011 8520.0016 913 0.0009 974 0.074 1035 0.0038 853 0.74 914 0.18 975 0.00151036 0.021 854 0.0064 915 1.6 976 0.0025 1037 0.012 855 0.0042 916 >10977 0.012 1038 0.034 856 0.022 917 0.24 978 0.0046 1039 0.31 857 0.014918 0.14 979 0.11 1040 No data 858 0.017 919 0.024 980 No data — — 8590.0044 920 0.31 981 No data — — 860 0.17 921 3.9 982 >0.3 — — 861 0.014922 >10 983 2.7 — — 862 0.24 923 >10 984 0.56 — — 863 0.0031 924 0.019985 2.3 — — 864 0.0044 925 0.66 986 >10 — — 865 0.0044 926 0.067 9870.0011 — — 866 0.014 927 0.12 988 0.0007 — — 867 0.0014 928 0.0036 9890.95 — — 868 0.015 929 0.1 990 0.31 — — 869 0.54 930 0.23 991 >0.01 — —870 0.14 931 0.14 992 0.54 — — 871 0.025 932 0.075 993 0.35 — — 8720.012 933 >0.1 994 9.5 — — 873 3.9 934 0.053 995 1.3 — — 874 0.35 9350.0038 996 0.76 — — 875 0.05 936 0.008 997 0.025 — —

The invention claimed is:
 1. A compound of the formula (I):

wherein Z is Het², optionally substituted on a ring carbon atom with oneor more substituents selected from the group consisting of halo, cyano,(C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,(C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(C₁-C₄)alkyl, (C₁-C₄)alkyl-S—,amino, (C₁-C₄)alkylamino, di(C₁-C₄)alkylamino, amino(C₁-C₄)alkyl,(C₁-C₄)alkylamino(C₁-C₄)alkyl, and di[(C₁-C₄)alkyl]amino(C₁-C₄)alkyl;and/or Het² is optionally substituted on a ring nitrogen atom with(C₁-C₄)alkyl, halo(C₁-C₄)alkyl and (C₃-C₈)cycloalkyl; with the provisothat Z is not tetrazolyl; Y¹, Y², Y³ and Y⁴ are each independently CH,CR¹ or N, provided that no more than two of Y¹, Y², Y³ and Y⁴ are N;each R¹ is independently selected from the group consisting of halo,cyano, amino, hydroxy, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,(C₁-C₄)alkoxy(C₁-C₄)alkyl, —C(O)H, —C(O)(C₁-C₄)alkyl, and —C(O)N(R²)₂;each R² is independently hydrogen, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,hydroxy(C₁-C₄)alkyl, or (C₃-C₆)cycloalkyl; or, where a nitrogen issubstituted with two R² groups, each independently selected from(C₁-C₄)alkyl, halo(C₁-C₄)alkyl, or hydroxy(C₁-C₄)alkyl, they may betaken together with the N atom to which they are attached to form a 4-to 6-membered ring which, when so formed, may therefore optionally besubstituted with hydrogen, alkyl, halo, hydroxy, hydroxyalkyl orhaloalkyl; B is phenyl or Het², wherein, when B is Het² it is attachedto the oxy linker at a ring carbon atom, and wherein B is optionallyfurther substituted on a ring carbon atom with one or more substituentsselected from the group consisting of halo, cyano, hydroxy,(C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy,cyano(C₁-C₄)alkyl, amino, (C₁-C₄)alkylamino, di(C₁-C₄)alkylamino,amino(C₁-C₄)alkyl, (C₁-C₄)alkylamino(C₁-C₄)alkyl,di[(C₁-C₄)alkyl]amino(C₁-C₄)alkyl, trifluoromethylthio,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, —C(O)R², —C(O)OR²,—OC(O)R², —C(O)—N(R²)₂, —CH₂—C(O)R², —CH₂—C(O)OR², —CH₂—OC(O)R²,—CH₂—C(O)—N(R²)₂, S(O)₂R², S(O)₂N(R²)₂, (C₃-C₈)cycloalkyl, and(C₃-C₈)cycloalkyl(C₁-C₄)alkyl; and/or Het² is optionally substituted ona ring nitrogen atom with a substituent selected from the groupconsisting of (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkoxy(C₁-C₄)alkyl, amino(C₁-C₄)alkyl,(C₁-C₄)alkylamino(C₁-C₄)alkyl, di[(C₁-C₄)alkyl]amino(C₁-C₄)alkyl,—CH₂—C(O)R², —CH₂—C(O)OR², —CH₂—C(O)—N(R²)₂, S(O)₂R², and S(O)₂N(R²)₂; Xis absent, —O—, methylene, ethylene, methylene-O—, or —O-methylene; C is(C₃-C₈)cycloalkyl, Het¹, phenyl, or Het², each optionally substituted ona ring carbon atom with one or more substituents selected from the groupconsisting of halo, cyano, hydroxy, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,(C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, N(R²)₂, (R²)₂N(C₁-C₄)alkyl,trifluoromethylthio, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl,—C(O)R², —C(O)OR², —OC(O)R², —C(O)—N(R²)₂, —CH₂—C(O)R², —CH₂—C(O)OR²,—CH₂—OC(O)R², —CH₂—C(O)—N(R²)₂, S(O)₂R², S(O)₂N(R²)₂,(C₃-C₈)cycloalkyl(C₁-C₄)alkyl, (C₃-C₈)cycloalkoxy,(C₃-C₈)cycloalkylamino, (C₃-C₈)cycloalkylamino(C₁-C₄)alkyl,(C₃-C₈)cycloalkyl(C₁-C₄)alkylamino,(C₃-C₈)cycloalkyl(C₁-C₄)alkylamino(C₁-C₄)alkyl,(C₃-C₈)cycloalkyl(C₁-C₄)alkoxy and D; and/or Het² is optionallysubstituted on a ring nitrogen atom with a substituent selected from thegroup consisting of hydroxy, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,amino(C₁-C₄)alkyl, (C₁-C₄)alkylamino(C₁-C₄)alkyl,di[(C₁-C₄)alkyl]amino(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl,(C₁-C₄)alkoxy(C₁-C₄)alkyl, —C(O)R², —C(O)OR², —CH₂—C(O)R², —CH₂—C(O)OR²,—CH₂—C(O)—N(R²)₂, S(O)₂R², and S(O)₂N(R²)₂ and D; D is phenyl, benzyl,(C₃-C₈)cycloalkyl, or Het¹, each optionally substituted on a carbon atomwith one or more substituents independently selected from the groupconsisting of halo, cyano, hydroxy, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl,(C₁-C₄)alkoxy, halo(C₁-C₄)alkoxy, amino, (C₁-C₄)alkylamino,di(C₁-C₄)alkylamino, amino(C₁-C₄)alkyl, (C₁-C₄)alkylamino(C₁-C₄)alkyl,di[(C₁-C₄)alkyl]amino(C₁-C₄)alkyl, trifluoromethylthio,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, —C(O)R², —C(O)OR²,—OC(O)R², —C(O)—N(R²)₂, —CH₂—C(O)R², —CH₂—C(O)OR², —CH₂—OC(O)R²,—CH₂—C(O)—N(R²)₂, S(O)₂R², and S(O)₂N(R²)₂; Het¹ is a 3- to 8-membered,saturated or partially unsaturated monocyclic heterocyclic groupcomprising one or two or three ring members selected from —NR³—, —O—,—C(O)— and —S(O)_(p)—; R³ is either the point of attachment to X or C togive

or R³ is selected from the group consisting of hydrogen, (C₁-C₄)alkyl,halo(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl,—C(O)(C₁-C₄)alkyl, —C(O)O(C₁-C₄)alkyl, —CH₂—C(O)O(C₁-C₄)alkyl,—CH₂—C(O)—N((C₁-C₄)alkyl)₂, S(O)₂R², S(O)₂N(R²)₂ and (C₃-C₈)cycloalkyl;p is 0, 1 or 2; and Het² is a 5- or 6-membered aromatic heterocyclicgroup comprising either (a) 1 to 4 nitrogen atoms, (b) one oxygen or onesulphur atom or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogenatoms; or a tautomer thereof, or a pharmaceutically acceptable salt ofthe compound of formula (I), or its tautomer; with the proviso that thecompound of formula (I) is not the following specific compound:


2. A compound of formula (I), or a pharmaceutically acceptable salt, ortautomer thereof, as claimed in claim 1, wherein Z is not isoxazolyl. 3.A compound of formula (I), or a pharmaceutically acceptable salt, ortautomer thereof, as claimed in claim 1, wherein Z is selected from thegroup consisting of 2-thiazolyl, 4-thiazolyl, 1-thia-3,4-diazolyl,1-thia-2,4-diazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl.4. A compound of formula (I), or a pharmaceutically acceptable salt, ortautomer thereof, as claimed in claim 1, wherein Y¹ is CR¹, and Y², Y³and Y⁴ are each CH; or Y¹ and Y³ are CR¹ and Y² and Y⁴ are CH.
 5. Acompound of formula (I), or a pharmaceutically acceptable salt, ortautomer thereof, as claimed in claim 4, wherein each R¹ isindependently selected from halo; cyano; (C₁-C₄)alkyl; halo(C₁-C₄)alkyl;(C₁-C₄)alkoxy; and —C(O)NH₂.
 6. A compound of formula (I), or apharmaceutically acceptable salt, or tautomer thereof, as claimed inclaim 1, wherein B is phenyl.
 7. A compound of formula (I), or apharmaceutically acceptable salt, or tautomer thereof, as claimed inclaim 6, wherein B is unsubstituted, or is substituted on a ring carbonwith one or two substituents independently selected from the groupconsisting of halo; halo(C₁-C₄)alkyl; or halo(C₁-C₄)alkoxy.
 8. Acompound of formula (I), or a pharmaceutically acceptable salt, ortautomer thereof, as claimed in claim 1, wherein C at the atom where itattaches to X, or directly to ring B if X is absent, is not furthersubstituted except that such an atom may be substituted by hydrogen ifchemically possible.
 9. A compound of formula (I), or a pharmaceuticallyacceptable salt, or tautomer thereof, as claimed in claim 1, wherein Cis selected from the group consisting of pyrazolyl; pyridinyl;pyridazinyl; pyrimidinyl; azetidinyl; piperidinyl; or tetrahydropyranyl.10. A compound of formula (I), or a pharmaceutically acceptable salt, ortautomer thereof, as claimed in claim 1, wherein X is absent.
 11. Acompound of formula (I), or a pharmaceutically acceptable salt, ortautomer thereof, as claimed in claim 1, which has the formula (Ib):

wherein R^(a) is independently selected from the group consisting ofhalo, cyano, hydroxy, (C₁-C₄)alkyl, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy,halo(C₁-C₄)alkoxy, cyano(C₁-C₄)alkyl, amino, (C₁-C₄)alkylamino,di(C₁-C₄)alkylamino, amino(C₁-C₄)alkyl, (C₁-C₄)alkylamino(C₁-C₄)alkyl,di[(C₁-C₄)alkyl]amino(C₁-C₄)alkyl, trifluoromethylthio,hydroxy(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)alkyl, —C(O)R², —C(O)OR²,—OC(O)R², —C(O)—N(R²)₂, —CH₂—C(O)R², —CH₂—C(O)OR², —CH₂—OC(O)R²,—CH₂—C(O)—N(R²)₂, S(O)₂R², S(O)₂N(R²)₂, (C₃-C₈)cycloalkyl, and(C₃-C₈)cycloalkyl(C₁-C₄)alkyl; and n is 0, 1 or
 2. 12. A compound offormula (I), or a pharmaceutically acceptable salt, or tautomer thereof,as claimed in claim 1, selected from the group consisting of:4-[2-(6-Aminopyridin-3-yl)-4-fluorophenoxy]-N-(5-chloro-1,3-thiazol-2-yl)-3-cyanobenzenesulfonamide;5-chloro-4-(4-chloro-2-piperidin-4-ylphenoxy)-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide;4-[4-Chloro-2-(1H-pyrazol-4-yl)phenoxy]-3-cyano-N-1,3-thiazol-2-ylbenzenesulfonamide;3-cyano-4-[2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethoxy)phenoxy]-N-1,3-thiazol-2-ylbenzenesulfonamide;4-(2-azetidin-3-yl-4-chlorophenoxy)-5-chloro-N-(5-chloro-1,3-thiazol-2-yl)-2-fluorobenzenesulfonamide;N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-[4-fluoro-2-(1H-pyrazol-4-yl)phenoxy]benzenesulfonamide;N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-[4-chloro-2-(1H-pyrazol-4-yl)phenoxy]benzenesulfonamide;4-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;4-[2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide;2,5-difluoro-4-[2-(1H-pyrazol-5-yl)-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;2,5-difluoro-4-[2-(1H-pyrazol-4-yl)-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;4-(4-chloro-2-(1H-pyrazol-4-yl)phenoxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;4-[2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;3-cyano-4-[2-(1H-pyrazol-5-yl)-4-(trifluoromethoxy)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;4-[2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;3-cyano-4-[2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethoxy)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;5-chloro-4-(4-chloro-2-piperidin-4-ylphenoxy)-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;3-cyano-4-[2-(5-methyl-1H-pyrazol-4-yl)-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;4-{2-[2-(aminomethyl)pyridin-4-yl]-4-chlorophenoxy}-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;3-Cyano-4-[2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;5-Chloro-2-fluoro-N-(5-fluoropyridin-2-yl)-4-[2-piperidin-4-yl-4-(trifluoromethyl)phenoxy]benzenesulfonamide;4-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy]-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;3-cyano-4-[2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;4-[2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;4-[4-chloro-5-fluoro-2-(1H-pyrazol-4-yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;2,5-difluoro-4-[2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;5-Chloro-2-fluoro-4-{4-fluoro-2-[1-(1-methylazetidin-3-yl)-1H-pyrazol-5-yl]phenoxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;5-Chloro-2-fluoro-4-{4-fluoro-2-[1-(1-methylazetidin-3-yl)-1H-pyrazol-5-yl]phenoxy}-N-1,3-thiazol-4-ylbenzenesulfonamide;4-[2-(1-Azetidin-3-yl-1H-pyrazol-5-yl)-4-fluorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide;4-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy]-3-cyano-N-1,3-thiazol-4-ylbenzenesulfonamide;4-[2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-fluorophenoxy]-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;4-{4-Chloro-2-[1-(1-methylazetidin-3-yl)-1H-pyrazol-5-yl]phenoxy}-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;4-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-pyrimidin-4-ylbenzenesulfonamide;5-chloro-4-[4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]-2-fluoro-N-pyrimidin-4-ylbenzenesulfonamide;4-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;3-cyano-4-[2-pyridazin-4-yl-4-(trifluoromethoxy)phenoxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;4-{4-Chloro-2-[2-(dimethylamino)pyridin-4-yl]phenoxy}-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;2,5-Difluoro-4-{2-[1-(1-methylazetidin-3-yl)-1H-pyrazol-5-yl]-4-(trifluoromethyl)phenoxy}-N-1,3-thiazol-4-ylbenzenesulfonamide;4-{4-Chloro-2-[1-(1-ethylazetidin-3-yl)-1H-pyrazol-5-yl]phenoxy}-3-cyano-N-1,3-thiazol-4-ylbenzenesulfonamide;4-{4-Chloro-2-[2-(cyclobutyloxy)pyridin-4-yl]phenoxy}-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;4-{4-Chloro-2-[2-(dimethylamino)pyridin-4-yl]phenoxy}-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;5-chloro-2-fluoro-4-[2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;4-[2-(3-amino-1H-pyrazol-4-yl)-4-(trifluoromethyl)phenoxy]-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;4-[2-(3-amino-1H-pyrazol-4-yl)-4-(trifluoromethyl)phenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide;4-[4-Chloro-2-(2-piperazin-1-ylpyrimidin-4-yl)phenoxy]-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;4-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-pyridazin-3-ylbenzenesulfonamide;4-{2-[2-(Azetidin-1-ylmethyl)pyridin-4-yl]-4-chlorophenoxy}-2,5-difluoro-N-1,3-thiazol-4-ylbenzenesulfonamide;3-Cyano-4-{2-[1-(1-ethylazetidin-3-yl)-1H-pyrazol-5-yl]-4-(trifluoromethyl)phenoxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;5-Chloro-2-fluoro-4-[5-fluoro-2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;3-Cyano-4-[5-fluoro-2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy]-N-1,2,4-thiodiazol-5-ylbenzenesulfonamide;4-[2-(3-amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-pyrimidin-4-ylbenzenesulfonamide;2-fluoro-5-methyl-4-[2-pyridazin-4-yl-4-(trifluoromethoxy)phenoxy]-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;4-[2-(3-amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-pyridazin-3-ylbenzenesulfonamide,and4-[2-(3-amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-pyrimidin-2-ylbenzenesulfonamide.13. A pharmaceutical composition comprising a compound of formula (I),or a pharmaceutically acceptable salt, or tautomer thereof, as claimedin claim 1, and one or more pharmaceutically acceptable excipients. 14.A pharmaceutical composition as claimed in claim 13 comprising one ormore additional therapeutic agents.
 15. A method of treating pain in amammal comprising administering to a mammal requiring such treatment aneffective amount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, or tautomer thereof, according to claim
 1. 16.4-[2-(2-Aminopyridin-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-pyridazin-3-ylbenzenesulfonamide;or a pharmaceutically acceptable salt or tautomer thereof. 17.4-[2-(3-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-pyrimidin-2-ylbenzenesulfonamide;or a pharmaceutically acceptable salt or tautomer thereof.
 18. A methodof treating pain according to claim 15 in which said pain is selectedfrom the group consisting of neuropathic pain, nociceptive pain andinflammatory pain.